c-Met modulators and methods of use

ABSTRACT

The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. More specifically, the invention provides quinazolines and quinolines which inhibit, regulate, and/or modulate kinase receptor, particularly c-Met, KDF, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of copending U.S. patent applicationSer. No. 11/753,514, filed May 24, 2007, which is a continuation of U.S.patent application Ser. No. 11/586,751, filed on Oct. 26, 2006, which isa continuation of U.S. patent application Ser. No. 10/573,336, filed onSep. 18, 2006, now abandoned, which is a national phase applicationunder 35 U.S.C. § 371 of International Patent Application No.PCT/US2004/031523, filed on Sep. 24, 2004, which claims the benefit ofU.S. Provisional Patent Application 60/506,181 filed on Sep. 26, 2003,and which also claims the benefit of U.S. Provisional Patent ApplicationNo. 60/535,377 filed on Jan. 9, 2004, and which also claims the benefitof U.S. Provisional Patent Application No. 60/577,384 filed on Jun. 4,2004, each of which is hereby incorporated by reference in its entiretyfor all purposes.

FIELD OF THE INVENTION

This invention relates to compounds for modulating protein kinaseenzymatic activity for modulating cellular activities such asproliferation, differentiation, programmed cell death, migration andchemoinvasion. Even more specifically, the invention relates toquinazolines and quinolines which inhibit, regulate and/or modulatekinase receptor signal transduction pathways related to the changes incellular activities as mentioned above, compositions which contain thesecompounds, methods of using them to treat kinase-dependent diseases andconditions, synthesis of the compounds as well as processes forformulating the compounds for pharmaceutical purposes.

BACKGROUND OF THE INVENTION

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation ofproteins, in particular, hydroxy groups on tyrosine, serine andthreonine residues of proteins. The consequences of this seeminglysimple activity are staggering; cell differentiation and proliferation;i.e., virtually all aspects of cell life in one-way or another depend onprotein kinase activity. Furthermore, abnormal protein kinase activityhas been related to a host of disorders, ranging from relativelynon-life threatening diseases such as psoriasis to extremely virulentdiseases such as glioblastoma (brain cancer).

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases have an extracellular, atransmembrane, and an intracellular portion, while non-receptor typetyrosine kinases are wholly intracellular.

Receptor-type tyrosine kinases are comprised of a large number oftransmembrane receptors with diverse biological activity. In fact, about20 different subfamilies of receptor-type tyrosine kinases have beenidentified. One tyrosine kinase subfamily, designated the HER subfamily,is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands of thissubfamily of receptors identified so far include epithelial growthfactor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.Another subfamily of these receptor-type tyrosine kinases is the insulinsubfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamilyincludes the PDGF-alpha and beta receptors, CSFIR, c-Kit and FLK-II.Then there is the FLK family, which is comprised of the kinase insertdomain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liverkinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1). The PDGFand FLK families are usually considered together due to the similaritiesof the two groups. For a detailed discussion of the receptor-typetyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994, which ishereby incorporated by reference.

The non-receptor type of tyrosine kinases is also comprised of numeroussubfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak,Jak, Ack, and LIMK. Each of these subfamilies is further sub-dividedinto varying receptors. For example, the Src subfamily is one of thelargest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk.The Src subfamily of enzymes has been linked to oncogenesis. For a moredetailed discussion of the non-receptor type of tyrosine kinases, seeBolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated byreference.

Since protein kinases and their ligands play critical roles in variouscellular activities, deregulation of protein kinase enzymatic activitycan lead to altered cellular properties, such as uncontrolled cellgrowth associated with cancer. In addition to oncological indications,altered kinase signaling is implicated in numerous other pathologicaldiseases. These include, but are not limited to: immunologicaldisorders, cardiovascular diseases, inflammatory diseases, anddegenerative diseases. Therefore, both receptor and non-receptor proteinkinases are attractive targets for small molecule drug discovery.

One particularly attractive goal for therapeutic use of kinasemodulation relates to oncological indications. For example, modulationof protein kinase activity for the treatment of cancer has beendemonstrated successfully with the FDA approval of Gleevec® (imatinibmesylate, produced by Novartis Pharmaceutical Corporation of EastHanover, N.J.) for the treatment of Chronic Myeloid Leukemia (CML) andgastrointestinal stroma cancers (GIST). Gleevec is a c-Kit and Ablkinase inhibitor.

Modulation (particularly inhibition) of cell proliferation andangiogenesis, two key cellular processes needed for tumor growth andsurvival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is anattractive goal for development of small-molecule drugs. Anti-angiogenictherapy represents a potentially important approach for the treatment ofsolid tumors and other diseases associated with dysregulatedvascularization, including ischemic coronary artery disease, diabeticretinopathy, psoriasis and rheumatoid arthritis. As well, cellantiproliferative agents are desirable to slow or stop the growth oftumors.

One particularly attractive target for small-molecule modulation, withrespect to antiangiogenic and antiproliferative activity is c-Met. Thekinase, c-Met, is the prototypic member of a subfamily of heterodimericreceptor tyrosine kinases (RTKs) which include Met, Ron and Sea.Expression of c-Met occurs in a wide variety of cell types includingepithelial, endothelial and mesenchymal cells where activation of thereceptor induces cell migration, invasion, proliferation and otherbiological activities associated with “invasive cell growth.” As such,signal transduction through c-Met receptor activation is responsible formany of the characteristics of tumor cells.

The endogenous ligand for c-Met is the hepatocyte growth factor (HGF), apotent inducer of angiogenesis, also known as “scatter factor” (SF).Binding of HGF to c-Met induces activation of the receptor viaautophosphorylation resulting in an increase of receptor dependentsignaling, which promotes cell growth and invasion. Anti-HGF antibodiesor HGF antagonists have been shown to inhibit tumor metastasis in vivo(See: Maulik et al Cytokine & Growth Factor Reviews 2002 13, 41-59).

Tumor growth progression requires the recruitment of new blood vesselsinto the tumor from preexisting vessels as well as invasion, adhesionand proliferation of malignant cells. Accordingly, c-Met overexpressionhas been demonstrated on a wide variety of tumor types including breast,colon, renal, lung, squamous cell myeloid leukemia, hemangiomas,melanomas, astrocytomas, and glioblastomas. Additionally activatingmutations in the kinase domain of c-Met have been identified inhereditary and sporadic renal papilloma and squamous cell carcinoma.(See: Maulik et al Cytokine & growth Factor reviews 2002 13, 41-59;Longati et al Curr Drug Targets 2001, 2, 41-55; Funakoshi et al ClinicaChimica Acta 2003 1-23). Thus modulation of c-Met is desirable as ameans to treat cancer and cancer-related disease.

The Eph receptors comprise the largest family of receptor tyrosinekinases and are divided into two groups, EphA and EphB, based on theirsequence homology. The ligands for the Eph receptors are ephrin, whichare membrane anchored. Ephrin A ligands bind preferentially to EphAreceptors whilst ephrin B ligands bind to EphB receptors. Binding ofephrin to Eph receptors causes receptor autophosphorylation andtypically requires a cell-cell interaction since both receptor andligand are membrane bound.

Overexpression of Eph receptors has been linked to increased cellproliferation in a variety of tumors (Zhou R 1998 Pharmacol Ther. 77,151-181; Kiyokawa E, Takai S, Tanaka M et al 1994 Cancer Res 54,3645-3650; Takai N Miyazaki T, Fujisawa K, Nasu K and Miyakawa. 2001Oncology reports 8, 567-573). The family of Eph receptor tyrosinekinases and their ephrin ligands play important roles in a variety ofprocesses during embryonic development and also in pathologicalangiogenesis and potentially metastasis. Therefore modulation of Ephreceptor kinase activity should provide means to treat or preventdisease states associated with abnormal cell proliferation such as thosedescribed above.

Inhibition of EGF, VEGF and ephrin signal transduction will prevent cellproliferation and angiogenesis, two key cellular processes needed fortumor growth and survival (Matter A. Drug Disc. Technol. 20016,1005-1024). EGF and VEGF receptors are previously described targets forsmall molecule inhibition. KDR and flt-4 are both VEGF receptors.

One particularly attractive target for small-molecule modulation isc-Kit. The protooncogene c-Kit was first identified as the oncogeniccomponent of the acutely transforming Hardy-Zuckerman 4-feline sarcomavirus (Besmer et al Nature 1986 320:415-421). c-Kit (also called stemcell factor receptor or steel factor receptor) is a type 3 receptortyrosine kinase (RTK) belonging to the platelet-derived growth factorreceptor subfamily. c-Kit binds the ligand stem cell factor (SCF), andtriggers its multiple signal transduction pathways including Src familykinases, phosphatidyl-inositol 3 kinase, the Ras-Raf-Map kinase cascade,and phospholipase C (Broudy et al Blood 1999 94: 1979-1986; Lennartssonet al Oncogene 1999 18: 5546-5553; Timokhina et al EMBO J. 1998 17;6250-6262; Chian et al Blood 2001 98(5)1365-1373; Blume-Jensen et alCurr Biol 1998 8:779-782; Kissel et al EMBO J. 2000 19:1312-1326;Lennartsson et al. Oncogene 1999 18: 5546-5553; Sue et al Blood,199892:1242-1149; Lev et al EMBO J. 1991 10:647-654). c-Kit is requiredfor normal hematopoiesis, melanonogenesis, and gametogenesis. c-Kit isexpressed in mast cells, immature myeloid cells, melanocytes, epithelialbreast cells and the interstitial cells of Cajal (ICC). In mast cells,it is required not only for the differentiation, maturation, chemotaxis,and haptotaxis but also for the promotion of survival and proliferation.

Mutations in c-Kit have been implicated in human disease. Mutations inthe juxtamembrane domain are found in many human gastrointestinalstromal tumors, and mutations in the kinase domain are found inmastocytosis, germ cell tumors, acute myeloid leukemia (AML), NKlymphoma, and other hematologic disorders (Hirota et al Science 1998279:577-580; Singer et al J Clin Oncol 2002 203898-3905; Longley et alProc Natl Aca Sci USA 1999: 1609-1614; Tian et al Am J Pathol 1999 154:1643-1647; Beghini et al Blood 2000 95:726-727; Hongyo et al Cancer Res2000 60:2345-2347). These mutations result in ligand-independenttyrosine kinase activity, autophosphorylation of c-Kit, uncontrolledcell proliferation, and stimulation of downstream signaling pathways.Overexpression of c-Kit and c-Kit ligand have also been described inother tumors including small-cell lung cancer, neuroblastomas,gynecological tumors, and colon carcinoma, which might result inautocrine or paracrine c-Kit activation.

The overexpression of c-Kit has also been implicated in the developmentof neoplasia associated with neurofibromatosis type 1 (NF1). Mutationsin the tumor suppressor gene NF1 lead to a deficiency in neurofibromin,a GTPase-activating protein for Ras. This deficiency results in abnormalproliferation of Schwann cells in the peripheral nervous system, andpredisposes affected individuals to peripheral nerve sheath tumors(neurofibromas), astrocytomas (optic pathway gliomas), learningdisabilities, seizures, strokes, macrocephaly, vascular abnormalities,and juvenile myelomonocytic leukemia (Lynch & Gutmann Neurol Clin 200220:841-865). Genetic experiments in mice demonstrate thathaploinsufficiency at NF1 partially rescues some of the phenotypesassociated with mutations in the gene for c-Kit, indicating that thesegenes function along a common developmental pathway (Ingram, et al. J.Exp Med 2000 191:181-187). Also, c-Kit is expressed in schwannoma cellsfrom NF1 patients, but not in normal schwann cells (Ryan et al. JNeurosci Res 1994 37:415-432). These data indicate that elevated c-Kitexpression and sensitivity to stem cell factor may play important rolesin the development of proliferative disorders associated with NF-1.Therefore, c-Kit inhibitors may be effective chemotherapeutic agents fortreating patients with NF-1.

GISTs are the most common mesenchymal tumors of the gastrointestinaltract, and they are generally resistant to chemotherapy and radiationtherapy. However, recent results with the c-Kit/BCR-Abl inhibitor STI571indicate that targeting c-Kit may be an effective therapeutic strategyfor this disease (Eisenberg & Mehren Expert Opin Pharmacother 20034:869-874). Malignant mast cell disease often suggests an extremely poorprognosis, and no reliable effective chemotherapeutic agents have beenidentified (Marone et al Leuk Res 2001 25:583-594). Systemic mast celldisorders have been treated with interferon-alpha, although theeffectiveness of this therapy has been variable (Lehmann & Lammle AnnHematol 1999 78:483-484; Butterfield Br J Dermatol 1998 138: 489-495).Therefore, activated c-Kit might serve as a therapeutic target in GISTsand mast cell disease, as well as other disorders associated withactivated c-Kit.

Flt-3 is normally expressed on hematopoietic progenitor cells and asubset of mature myeloid and lymphoid cells, where it modulates cellsurvival and proliferation. Flt-3 is constitutively activated viamutation, either in the juxtamembrane region or in the activation loopof the kinase domain, in a large proportion of patients with AML (ReillyLeuk Lymphoma 2003 44: 1-7). Also, mutations in flt-3 are significantlycorrelated with poor prognosis in AML patients (Sawyers Cancer Cell 20021: 413-415).

Accordingly, the identification of small-molecule compounds thatspecifically inhibit, regulate and/or modulate the signal transductionof kinases, particularly including c-Met, KDR, c-Kit, flt-3, and flt-4,is desirable as a means to treat or prevent disease states associatedwith abnormal cell proliferation and angiogenesis, and is an object ofthis invention.

Quinolines and quinazolines bearing substitution, for example at thetwo, four, six and seven positions of their fused ring system have beenshown to be particularly attractive targets for kinase inhibition by anumber of groups. Conventional quinoline and quinazoline kinaseinhibitors typically have fairly simple substitution about the quinolineor quinazoline fused ten-membered ring system, but recently more complexmolecules are being disclosed. For example, we have previouslydisclosed, in U.S. provisional patent applications 60/506,181 and60/535,377 which are both incorporated by reference herein in theirentirety for all purposes, that certain quinolines and quinazolines areparticularly well suited as kinase modulators, more particularlyinhibitors of for example c-Met, KDR, c-Kit, flt-3, and flt-4. Thesemolecules in some cases are particularly complex and although they canbe made via conventional methods, more efficient routes are desirable,especially in a pharmaceutical setting.

International patent application publication no. WO 01/21597 disclosessubstituted quinazolines linked, via a heteroatom, to an optionallysubstituted aromatic ring containing at least one nitrogen atom. WO01/21597 states that the disclosed compounds inhibit aurora 2 kinase andare useful in the treatment of proliferative disease such as cancer.U.S. patent application publication no. US 2004/0242603 disclosessubstituted quinolines and quinazolines linked, via a heteroatom, to asubstituted phenylene. US 2004/0242603 states that the disclosedcompounds have autophosphorylation inhibitory activity and antitumoractivity.

International patent application publication no. WO 2005/005389discloses bivalent malonamide derivatives, including derivatives inwhich substituted aryl substituents are bonded directly to the nitrogenatoms on either side of the malonamide moiety. WO 2005/005389 statesthat the disclosed compounds are inhibitors of raf kinase.

Conventional methods of making quinolines and quinazolines with theaforementioned substitution patterns usually involve linear constructionof a quinoline or quinazoline template upon which relatively simplesubstitutions are appended. With the advent of more complex substitutionabout such quinolines and quinazolines (vide supra), for example sidechains containing cyclic and bicyclic systems with multiple functionalgroups, conventional methods of synthesis become problematic due to thelinear or serial reactions used. Indeed, as such molecules become morecomplex and the utility of such complex groups is realized, thequinoline and quinazoline ring system becomes more of a sub-structurethan a main structure of such inhibitors. Thus it is desirable to findmore efficient methods of synthesis, particularly convergent syntheseswhich are an object of this invention.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds for modulatingkinase activity and methods of treating diseases mediated by kinaseactivity utilizing the compounds and pharmaceutical compositionsthereof. Diseases mediated by kinase activity include, but are notlimited to, diseases characterized in part by migration, invasion,proliferation and other biological activities associated with invasivecell growth. In particular to this invention is modulation, even moreparticularly inhibition, of c-Met, KDR, c-Kit, flt-3, and flt-4.

In another aspect, the invention provides methods of screening formodulators of c-Met, KDR, c-Kit, flt-3, and flt-4 activity. The methodscomprise combining a composition of the invention, a kinase, e.g. c-Met,KDR, c-Kit, flt-3, or flt-4, and at least one candidate agent anddetermining the effect of the candidate agent on the c-Met, KDR, c-Kit,flt-3, or flt-4, activity.

In yet another aspect, the invention also provides pharmaceutical kitscomprising one or more containers filled with one or more of theingredients of pharmaceutical compounds and/or compositions of thepresent invention, including, one or more kinase, e.g. c-Met, KDR,c-Kit, flt-3, or flt-4, enzyme activity modulators as described herein.Such kits can also include, for example, other compounds and/orcompositions (e.g., diluents, permeation enhancers, lubricants, and thelike), a device(s) for administering the compounds and/or compositions,and written instructions in a form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals or biologicalproducts, which instructions can also reflects approval by the agency ofmanufacture, use or sale for human administration.

In another aspect, the invention also provides a diagnostic agentcomprising a compound of the invention and, optionally, pharmaceuticallyacceptable adjuvants and excipients.

In still yet another aspect, the present invention provides processesfor making compounds, and pharmaceutical compositions thereof, formodulating kinase activity and treating diseases mediated by kinaseactivity. In particular to this invention are methods for makingquinolines and quinazolines used for modulation of kinase activity, evenmore particularly inhibition of kinase activity, and yet even moreparticularly inhibition of c-Met, KDR, c-Kit, flt-3, and flt-4.

These and other features and advantages of the present invention will bedescribed in more detail below with reference to the associateddrawings.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of the invention are used to treat diseases associatedwith abnormal and or unregulated cellular activities. Disease stateswhich can be treated by the methods and compositions provided hereininclude, but are not limited to, cancer (further discussed below),immunological disorders such as rheumatoid arthritis, graft-hostdiseases, multiple sclerosis, psoriasis; cardiovascular diseases such asartherosclerosis, myocardioinfarction, ischemia, stroke and restenosis;other inflammatory and degenerative diseases such as interboweldiseases, osteoarthritus, macular degeneration, diabetic retinopathy.

It is appreciated that in some cases the cells may not be in a hyper- orhypo-proliferative and/or migratory state (abnormal state) and stillrequire treatment. For example, during wound healing, the cells may beproliferating “normally”, but proliferation and migration enhancementmay be desired. Alternatively, reduction in “normal” cell proliferationand/or migration rate may be desired.

Thus, in one aspect the present invention comprises a compound formodulating kinase activity according to Formula I,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,wherein,R¹ is selected from —H, halogen, —OR³, —NO₂, —NH₂, —NR³R⁴, andoptionally substituted lower alkyl;A¹ is selected from ═N—, ═C(H)—, and ═C(CN)—;Z is selected from —S(O)₀₋₂—, —O—, and —NR⁵—;Ar is either a group of formula II, or of formula III,

wherein,R² is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³,—NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally substituted loweralkyl;q is 0 to 4;G is a group —B-L-T, wherein

-   -   B is selected from absent, —N(R¹³)—, —N(SO₂R¹³)—, —O—,        —S(O)₀₋₂—, and —C(═O)—;    -   L is selected from absent, —C(═S)N(R¹³)—, —C(═NR¹⁴)N(R¹³)—,        —SO₂N(R¹³)—, —SO₂—, —C(═O)N(R¹³)—, —N(R¹³)—,        —C(═O)C₁₋₂alkylN(R¹³)—, —N(R¹³)C₁₋₂alkylC(═O)—,        —C(═O)C₀₋₁alkylC(═O)N(R¹³)—, —C₀₋₄alkylene-,        —C(═O)C₀₋₁alkylC(═O)OR³—, —C(═NR¹⁴)C₀₋₁alkylC(═O)—, —C(═O)—,        —C(═O)C₀₋₁alkylC(═O)—, and an optionally substituted four to        six-membered heterocyclyl containing between one and three        annular heteroatoms including at least one nitrogen; and    -   T is selected from —H, —R³, —C₀₋₄alkyl, —C₀₋₄alkylQ,        —OC₀₋₄alkylQ, —C₀₋₄alkylOQ, —N(R¹³)C₀₋₄alkylQ, —SO₂C₀₋₄alkylQ,        —C(═O)C₀₋₄alkylQ, —C₀₋₄alkylN(R¹³)Q, and —C(═O)N(R¹³)C₀₋₄alkylQ,        wherein each of the aforementioned C₀₋₄alkyl is optionally        substituted;        J is selected from —S(O)₀₋₂—, —O—, and —NR¹⁵—;

R³ is —H or R⁴;

R⁴ is selected from optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted lower arylalkyl, optionallysubstituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl; orR³ and R⁴, when taken together with a common nitrogen to which they areattached, form an optionally substituted five- to seven-memberedheterocyclyl, said optionally substituted five- to seven-memberedheterocyclyl optionally containing at least one additional annularheteroatom selected from N, O, S, and P;A² and A³ are each independently selected from ═N—, ═C(R²)—;R⁵ is —H or optionally substituted lower alkyl;D is selected from —O—, —S(O)₀₋₂—, and —NR¹⁵—;R⁵⁰ is either R³, or according to formula IV;

wherein X¹, X², and optionally X³, represent the atoms of a saturatedbridged ring system, said saturated bridged ring system comprising up tofour annular heteroatoms represented by any of X¹, X², and X³; wherein,

-   -   each X¹ is independently selected from —C(R⁶)R⁷—, —O—,        —S(O)₀₋₂—, and —NR⁸—;    -   each X² is independently an optionally substituted bridgehead        methine or a bridgehead nitrogen;    -   each X³ is independently selected from —C(R⁶)R⁷—, —O—,        —S(O)₀₋₂—, and —NR⁸—;        Y is either:    -   an optionally substituted lower alkylene linker, between D and        either 1) any annular atom of the saturated bridged ring system,        except X² when X² is a bridgehead nitrogen, or 2) any        heteroatom, represented by any of R⁶ or R⁷; provided there are        at least two carbon atoms between D and any annular heteroatom        of the saturated bridged ring system or any heteroatom        represented by any of R⁶ or R⁷;    -   or Y is absent, when Y is absent, said saturated bridged ring        system, is directly attached to D via an annular carbon of said        saturated bridged ring system, unless D is —SO₂—, in which case        said saturated bridged ring system, is directly attached to D        via an any annular atom of said saturated bridged ring system;        m and p are each independently 1-4;        n is 0-2, when n=0, then there is a single bond between the two        bridgehead X²'s;        R⁶ and R⁷ are each independently selected from —H, halogen,        trihalomethyl, —CN, —NH₂, —NO₂, —OR³, —NR³R⁴, —S(O)₀₋₂R⁴,        —SO₂NR³R⁴, —CO₂R³, —C(O)NR³R⁴, —N(R³)SO₂R⁴, —N(R³)C(O)R³,        —NCO₂R³, —C(O)R³, optionally substituted lower alkyl, optionally        substituted aryl, optionally substituted lower arylalkyl,        optionally substituted heterocyclyl, optionally substituted        lower heterocyclylalkyl, and a bond to either Y or D; or        R⁶ and R⁷, when taken together are oxo; or        R⁶ and R⁷, when taken together with a common carbon to which        they are attached, form a optionally substituted three- to        seven-membered spirocyclyl, said optionally substituted three-        to seven-membered spirocyclyl optionally containing at least one        additional annular heteroatom selected from N, O, S, and P;        R⁸ is selected from —R³, Y, —SO₂NR³R⁴, —CO₂R⁴, —C(O)NR³R³,        —SO₂R⁴, and —C(O)R³;        R¹³ is selected from —H, —C(═O)R³, —C(═O)OR³, —C(═O)SR³, —SO₂R⁴,        —C(═O)N(R³)R³, and optionally substituted lower alkyl,        two R¹³, together with the atom or atoms to which they are        attached, can combine to form a heteroalicyclic optionally        substituted with between one and four of R⁶⁰, said        heteroalicyclic can have up to four annular heteroatoms, and        said heteroalicyclic can have an aryl or heteroaryl fused        thereto, in which case said aryl or heteroaryl is optionally        substituted with an additional one to four of R⁶⁰;        R¹⁴ is selected from —H, —NO₂, —NH₂, —N(R³)R⁴, —CN, —OR³,        optionally substituted lower alkyl, optionally substituted        heteroalicyclylalkyl, optionally substituted aryl, optionally        substituted arylalkyl and optionally substituted        heteroalicyclic;        R¹⁵ is a group -M¹-M², wherein M¹ is selected from absent,        —C(═S)N(R¹³)—, —C(═NR¹⁴)N(R¹³)—, —SO₂N(R¹³)—, —SO₂—,        —C(═O)N(R¹³)—, —C(═O)C(═O)N(R¹³)—, —C₀₋₄alkylene-, —C(═O)—, and        an optionally substituted four to six-membered heterocyclyl        annular containing between one and three heteroatoms including        at least one nitrogen; and M² is selected from —H, —C₀₋₆alkyl,        alkoxy, —C(═O)C₀₋₄alkylQ, —C₀₋₄alkylQ, —OC₀₋₄alkylQ-,        —N(R¹³)C₀₋₄alkylQ-, and —C(═O)N(R¹³)C₀₋₄alkylQ; and        Q is a five- to ten-membered ring system, optionally substituted        with between zero and four of R²⁰;        R²⁰ is selected from —H, halogen, trihalomethyl, —CN, —NO₂,        —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,        —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³ and optionally        substituted lower alkyl;        R⁶⁰ is selected from —H, halogen, trihalomethyl, —CN, —NO₂,        —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,        —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally        substituted lower alkyl, optionally substituted aryl, optionally        substituted heteroarylalkyl, and optionally substituted        arylalkyl;        two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo;        with the proviso, only when Ar is according to formula II, if Y        is a C₁₋₆ alkylene; Z is —NH— or —N(CH₃)—; R¹ is a C₁₋₆alkyl        optionally substituted in the 2-position by —OH or a C₁₋₄alkoxy        group; R² is —H or halogen; n=0; and the atoms, X¹, of one        bridge of the saturated bridged ring system, when combined with        both bridgehead atoms, X², of the saturated bridged ring system,        represent:    -   1) either a pyrrolidine or a piperidine, and any atom, X¹ or X²,        of either of said pyrrolidine or said piperidine is attached to        Y, then the other bridge of said saturated bridged ring system        cannot be any one of —OC(O)CH₂—, —CH₂OC(O)—, —OC(O)CH₂CH₂—,        —CH₂OC(O)CH₂—, —CH₂CH₂OC(O)—, —OC(O)CH₂NH—,        —OC(O)CH₂N(C₁₋₄alkyl)-, and —OC(O)CH₂O—; or    -   2) either a piperazine or a 4-(C₁₋₄alkyl)-piperazine, and any        atom, X¹ or X², of either of said piperazine or said        4-(C₁₋₄alkyl)-piperazine is attached to Y, then the other bridge        of said saturated bridged ring system, only when attached via        the 2- and the 3-position of either of said piperazine or said        4-(C₁₋₄alkyl)-piperazine, cannot be one of —CH₂OC(O)CH₂—,        —CH₂CH₂OC(O)—, and either of the two aforementioned bridges        optionally substituted by one or two C₁₋₂alkyl groups; or    -   3) a piperazine, and any atom, X¹ or X², of said piperazine is        attached to Y, then the other bridge of said saturated bridged        ring system, only when attached via the 3- and the 4-position of        said piperazine, cannot be one of —C(O)OCH₂CH₂—, —CH₂OC(O)CH₂—,        and either of the two aforementioned bridges optionally        substituted by one or two C₁₋₂alkyl groups, and only when either        of the two aforementioned bridges are attached to the 3-position        of said piperazine via their left-hand end as depicted above; or    -   4) a 2-oxomorpholine, said 2-oxomorpholine attached to Y via its        4-position, then the other bridge of said saturated bridged ring        system, only when attached via the 5- and the 6-position of said        2-oxomorpholine, cannot be one of —(CH₂)_(g)—, —CH₂WCH₂—,        —CH₂WCH₂CH₂—, and —CH₂CH₂WCH₂—, wherein W is —O—, —S(O)₀₋₂—,        —NH—, or —N(C₁₋₄alkyl)- wherein g is 2, 3, or 4;        and with the proviso that when Z is —O—, Ar is according to        formula II, and the portion of G directly attached to Ar is        selected from:

then R⁵⁰ must be of formula IV;and with the proviso that when Ar is phenylene or substituted phenylene,Z is —S(O)₀₋₂— or —O—, then the portion of G directly attached to Arcannot contain

when R⁷⁰ is selected from —H, C₁₋₄alkyl, and C₁₋₄alkoxyl.

In one example, the compound is according to Formula I, wherein Z iseither —O— or —NR⁵—.

In another example, the compound is according to Formula I, wherein Z iseither —O— or —NR⁵— and G is selected from the following:

wherein Q, R²⁰, and R¹³ are as defined above; each E is selected from—O—, —N(R¹³)—, —CH₂—, and —S(O)₀₋₂—; M is selected from —O—, —N(R¹³)—,—CH₂—, and —C(═O)N(R¹³)—; each V is independently either ═N— or ═C(H)—;each methylene in any of the above formulae is independently optionallysubstituted with R²⁵; and R²⁵ is selected from halogen, trihalomethyl,—CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³,—C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionallysubstituted aryl, optionally substituted arylalkyl, heteroarylalkyl, andoptionally substituted lower alkyl; two of R²⁵, together with the carbonor carbons to which they are attached, can combine to form a three- toseven-membered alicyclic or heteroalicyclic, two of R²⁵ on a singlecarbon can be oxo.

In another example, the compound is according to the precedingparagraph, wherein Ar is according to one of formula Ia, IIb, and IIIa.

In another example, the compound is according to the precedingparagraph, wherein D is —O— and R¹ is —OR³.

In another example, the compound is according to the precedingparagraph, wherein —O—R⁵⁰ and R¹ are interchangeably located at the6-position and 7-position of the quinazoline or quinoline according toformula I.

In another example, the compound is according to the precedingparagraph, wherein R¹ is —OH or —OC₁₋₆ alkyl.

In another example, the compound is according to the precedingparagraph, wherein A¹ is ═N— or ═C(H)—.

In another example, the compound is according to the precedingparagraph, wherein G is selected from:

wherein Q, R²⁰, R¹³, E, and R⁶⁰ are as defined above; each methylene inany of the above formulae, other than those in a depicted ring, isindependently optionally substituted with R²⁵; and R²⁵ is selected fromhalogen, trihalomethyl, oxo, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³,—SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³,—C(O)R³, optionally substituted aryl, optionally substituted arylalkyl,heteroarylalkyl, and optionally substituted lower alkyl; two of R²⁵,together with the carbon or carbons to which they are attached, cancombine to form a three- to seven-membered alicyclic or heteroalicyclic.

In another example, the compound is according to the precedingparagraph, wherein Q is selected from:

wherein R²⁰ is defined as above, and P is a five- to seven-memberedring, including the two shared carbons of the aromatic ring to which Pis fused, P optionally containing between one and three heteroatoms.

In another example, the compound is according to the precedingparagraph, wherein Ar is according to formula IIa, and G is selectedfrom:

wherein Q, R²⁰, R¹³, E, and R⁶⁰ are as defined above, and each methylenein any of the above formulae, other than those in a depicted ring, isindependently optionally substituted with R²⁵; and R²⁵ is selected fromhalogen, trihalomethyl, oxo, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³,—SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³,—C(O)R³, optionally substituted aryl, optionally substituted arylalkyl,heteroarylalkyl, and optionally substituted lower alkyl; two of R²⁵,together with the carbon or carbons to which they are attached, cancombine to form a three- to seven-membered alicyclic or heteroalicyclic.

In another example, the compound is as defined two paragraphs above, andG is selected from:

wherein Q, R²⁰, R¹³, E, and R⁶⁰ are as defined above, and each methylenein any of the above formulae, other than those depicted in a ring, isindependently optionally substituted with R²⁵; and R²⁵ is selected fromhalogen, trihalomethyl, oxo, —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³,—SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³,—C(O)R³, optionally substituted aryl, optionally substituted arylalkyl,heteroarylalkyl, and optionally substituted lower alkyl; two of R²⁵,together with the carbon or carbons to which they are attached, cancombine to form a three- to seven-membered alicyclic or heteroalicyclic.

In another example, the compound is according to either of the twopreceding paragraphs, wherein the methylene between the two carbonyls ofthe depicted formulae is di-substituted with either optionallysubstituted lower alkyl, or an optionally substituted spirocycle.

In another example, the compound is as defined three paragraphs above oras defined two paragraphs above, wherein R⁵⁰ is a heteroalicylic or aC₁₋₆alkyl-heteroalicylic.

In another example, the compound is according to the precedingparagraph, wherein at least one of R² is halogen.

In another example, the compound is as defined two paragraphs above,wherein R⁵⁰ is according to formula IV.

In another example, the compound is according to the precedingparagraph, wherein the saturated bridged ring system according toformula IV has a geometry selected from the group consisting of [4.4.0],[4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3], [3.3.2],[3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].

In another example, the compound is according to the precedingparagraph, wherein Y is selected from —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂—, —CH₂—, and absent.

In another example, the compound is according to the precedingparagraph, wherein n is 0 and the saturated bridged ring systemaccording to formula IV has a geometry selected from the groupconsisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and[3.1.0].

In another example, the compound is according to the precedingparagraph, wherein said saturated bridged ring system contains at leastone annular nitrogen or at least one annular oxygen.

In another example, the compound is according to the precedingparagraph, wherein said saturated bridged ring system contains —NR⁸—,wherein R⁸ is selected from —H. optionally substituted lower alkyl,—CO₂R³, —C(O)NR³R³, —SO₂R³, and —C(O)R³.

In another example, the compound is as defined two paragraphs above,wherein said saturated bridged ring system is of formula V,

wherein U¹ is selected from —O—, —S(O)₀₋₂—, —NR⁸—, —CR⁶R⁷—, and absent;and e is 0 or 1.

In another example, the compound is according to the precedingparagraph, wherein Y is —CH₂—.

In another example, the compound is according to the precedingparagraph, wherein U¹ is —NR⁸—, wherein R⁸ is selected from —H,optionally substituted lower alkyl, —CO₂R³, —C(O)NR³R³, —SO₂R³, and—C(O)R³.

In another example, the compound is as defined two paragraphs above,wherein U¹ is —O—.

In another example, the compound is as defined three paragraphs above,wherein U¹ is absent.

In another example, the saturated bridged ring system is according toformula IV with a geometry selected from the group consisting of[4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and [3.1.0] andcontains at least one annular nitrogen or at least one annular oxygen,wherein n is 0 and Y is selected from —CH₂CH₂—, —CH₂—, and absent.

In another example, the compound is according to the precedingparagraph, wherein said saturated bridged ring system is of formula VI,

-   -   wherein R⁹, R¹⁰, and R¹¹ are each independently selected from        —H, and —OR¹²; or    -   R⁹ is selected from —H, and —OR¹², and R¹⁰ and R¹¹, when taken        together, are either an optionally substituted alkylidene or an        oxo;    -   R¹² is selected from —H, —C(O)R³, optionally substituted lower        alkylidyne, optionally substituted lower arylalkylidyne,        optionally substituted lower heterocyclylalkylidyne, optionally        substituted lower alkylidene, optionally substituted lower        alkylidenearyl, optionally substituted lower        alkylideneheterocyclyl, optionally substituted lower alkyl,        optionally substituted lower alkylaryl, optionally substituted        aryl, optionally substituted lower heterocyclylalkyl, and        optionally substituted heterocyclyl;    -   or two R¹²'s, when taken together, form 1) a corresponding        spirocyclic ketal when said two R¹²'s stem from R¹⁰ and R¹¹,        or 2) a corresponding cyclic ketal when said two R¹²'s stem from        R⁹ and one of R¹⁰ and R¹¹.

In another example, the compound is according to the precedingparagraph, wherein one of R¹⁰ and R¹¹ is —OR¹², wherein R¹² is selectedfrom —H, —C(O)R³, and optionally substituted lower alkyl; and R⁹ and theother of R¹⁰ and R¹¹ are both —H.

In another example, the compound is according to the precedingparagraph, wherein Y is either —CH₂— or absent.

In another example, the compound is according to the precedingparagraph, wherein R⁹ is an alkyl group containing at least one fluorinesubstitution thereon.

In another example, the saturated bridged ring system is of formula VII,wherein R⁸ is selected from —H, optionally substituted lower alkyl,—CO₂R³, C(O)NR³R³, —SO₂R³, and —C(O)R³.

In another example, the compound is according to the precedingparagraph, wherein Y is either —CH₂— or absent.

In another example, the compound is according to the precedingparagraph, wherein R⁸ is methyl or ethyl.

In another example, the saturated bridged ring system is of formulaVIII.

wherein R⁸ is selected from —H, optionally substituted lower alkyl,—CO₂R³, —C(O)NR³R³, —SO₂R³, and —C(O)R³.

In another example, the compound is according to the precedingparagraph, wherein Y is —CH₂—.

In another example, the compound is according to the precedingparagraph, wherein R⁸ is methyl or ethyl.

In another example, the said saturated bridged ring system is of formulaIX

wherein U² is selected from —O—, —S(O)₀₋₂—, —NR⁸—, —CR⁶R⁷—, and absent.

In another example, the compound is according to the precedingparagraph, wherein R³ of formula IX is selected from —H and optionallysubstituted alkyl.

In another example, the compound is according to the precedingparagraph, wherein U² is either —CR⁶R⁷— or absent.

In another example, the compound is according to the precedingparagraph, wherein U² is either —CH₂— or absent.

In another example, the compound is according to the precedingparagraph, wherein Y is —CH₂—.

In another example, the saturated bridged ring system is according toformula X, wherein R⁸ is selected from —H, optionally substituted loweralkyl, —CO₂R³, C(O)NR³R³, —SO₂R³, and —C(O)R³.

In another example, the compound is according to the precedingparagraph, wherein R⁸ is methyl or ethyl.

In another example, the compound is selected from Table 1.

TABLE 1 Entry Name Structure 1 N-[({3-fluoro-4-[(6-(methyloxy)-7-{[(3aR,6aS)- octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4- yl)oxy]phenyl}amino) carbonothioyl]-2-phenylacetamide

2 N-{[(3-fluoro-4-{[7- ({[3aR,6aS)-2- methyloxtahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6- (methyloxy)quinazolin-4- yl]oxy}phenyl)amino]carbonothioyl}-2- phenylacetamide

3 N-{[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)(methyl)amino] carbonothioyl}-2- phenylacetamide

4 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)imidazolin-2-one

5 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3-(phenylmethyl)imidazolidin- 2-one

6 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3-(phenylacetyl)imidazolidin-2- one

7 ethyl [(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)amino](oxo)acetate

8 N-{[(4-{[6,7 bis(methyloxy)quinazolin-4- yl]amino}-3-fluorophenyl)amino]carbonothioyl}-2- phenylacetamide

9 N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N-methyl-N-(2-phenylethyl) sulfamide

10 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3-(phenylmethyl)-1,2,4- oxadiazol-5-amine

11 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)piperidin-2-one

12 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(phenylmethyl)ethanediamide

13 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-4-phenyl-1,3-thiazol-2-amine

14 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide

15 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-1-phenylmethanesulfonamide

16 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-2-phenylethanesulfonamide

17 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N- (phenylmethyl)benzenesulfonamide

18 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N-(phenylmethyl) benzenesulfonamide

19 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(2-phenylethyl) benzenesulfonamide

20 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N-(2-phenylethyl) benzenesulfonamide

21 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-(3-phenylpropyl) benzenesulfonamide

22 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)pyrrolidin-2-one

23 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl(phenylmethyl)carbamate

24 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl (2-phenylethyl)carbamate

25 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-methyl-N-(3-phenylpropyl) benzenesulfonamide

26 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-phenylethanediamide

27 N-{[(3-fluoro-4-{[7-{[(2- methyloctahydrocyclopenta[c]pyrrol-5-yl)methyl]oxy}-6- (methyloxy)quinolin-4- yl]oxy}phenyl)amino]carbonothioyl}-2- phenylacetamide

28 N-[(Z)-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)amino](imino)methyl]-2- phenylacetamide

29 4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluoro-N-[2-(phenyloxy)ethyl] benzenesulfonamide

30 N,N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-bis-(3-phenylpropane-1- sulfonamide

31 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3-phenylpropane-1-sulfonamide

32 N2-[(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)sulfonyl]-N1- phenylglycinamide

33 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-2-phenylacetamide

34 N-{[(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)amino]carbonothioyl}-2- phenylacetamide

35 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-1,3-benzothiazol-2- amine

36 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3-benzothiazol-2-amine

37 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2- phenylacetamide

38 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(2-morpholin-4- ylethyl)ethanediamide

39 benzyl-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-methyl}- carbamic acid tert-butyl ester

40 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-(phenylmethyl)glycinamide

41 N2-acetyl-N1-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N2- (phenylmethyl)glycinamide

42 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-1,3-benzothiazol-2-yl)-2-phenylacetamide

43 benzyl-{[6-(6,7-dimethoxy- quinolin-4-yloxy)-pyridin-3-ylcarbamoyl]-methyl}- carbamic acid tert-butyl ester

44 N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2-(phenylmethyl)glycinamide

45 B2-acetyl-N1-(6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N2- (phenylmethyl)glycinamide

46 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-3-phenylpropanamide

47 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-4-phenylbutanamide

48 N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N2-methyl-N2- (phenylmethyl)glycinamaide

49 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-{2-[4-(methyloxy) phenyl]ethyl}ethanediamide

50 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-methyl-N2-(phenylmethyl) glycinamide

51 4-[(2-amino-1,3-benzothiazol- 6-yl)oxy]-6,7-bis(methyloxy)-1-(2-oxo-2-phenylethyl) quinolinium

52 N-{[(4-{[6,7- bis(methyloxy)quinolin-4- yl]amino}phenyl)amino]carbonothioyl}-2- phenylacetamide

53 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-3- phenylproanamide

54 N-{[(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)amino]carbonothioyl}-2- phenylacetamide

55 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(2,3-dihydro-1H-inden-1- yl)ethanediamide

56 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(2,3-dihydro-1H-inden-2- yl)ethanediamide

57 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-tetrahydronaphthalen- 1-yl)ethandiamide

58 N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N-(2-phenylethyl)-N- (phenylmethyl)sulfamide

59 N1-(4-{[(6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-(trifluoroacetyl)glycinamide

60 N-{[4-(6,7-dimethoxy- quinolin-4-yloxy)-3-fluoro-phenylcarbamoyl]-methyl}- benzamide

61 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridin-3-yl)-N′-(4-fluorophenyl)propanediamide

62 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-[(2S)-1,2,3,4- tetrahydronaphthalen-2- yl]ethandiamide

63 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-[2-(4- methylphenyl)ethyl]ethandi amide

64 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(2-phenylpropyl) ethanediamide

65 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-[2-(4-chlorophenyl) ethyl]ethanediamide

66 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N,N′-bis(phenylmethyl)sulfamide

67 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N,N′-bis(2-phenylethyl)sulfamide

68 ethyl [(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)amino](oxo)acetate

69 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(2-phenylethyl) ethanediamide

70 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(4-fluorophenyl) propanediamide

71 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4-tetrahydronaphthalen- 2-yl)ethanediamide

72 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-[2-(1-methylpyrrolidin-2- yl)ethyl]ethanediamide

73 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-[2-(phenyloxy) ethyl]ethanediamide

74 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-[2-hydroxy-1- (phenylmethyl)ethyl]urea

75 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-3-[(4-methylphenyl)sulfonyl]-4- (phenylmethyl)imidazolidin- 2-one

76 N′-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N-methyl-N-(2-phenylethyl) ethanediamide

77 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-{[3-(trifluoromethyl) phenyl]methyl}ethanediamide

78 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-{2-[3-(trifluoromethyl) phenyl]ethyl}ethanediamide

79 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-3-oxo-4- phenylbutanamide

80 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-2-[3-(trifluoromethyl) phenyl]acetamide

81 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-[2-(phenyloxy)ethyl]-1,3- benzothiazol-2-amine

82 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2-piperidin-1-ylethyl)-1,3- benzothiazol-2-amine

83 6-{[6,7- bis(methylpxu)quinolin-4- yl]oxy}-5-fluoro-N-methyl-N-(2-phenylethyl)-1,3- benzothiazol-2-amine

84 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-(2-pyrrolidin-1-ylethyl)-1,3- benzothiazol-2-amine

85 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{[3-(trifluoromethyl)phenyl]meth yl}-1,3-benzothiazol-2-amine

86 6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-N-{2-[3-(trifluoromethyl)phenyl]ethyl}- 1,3-benzothiazol-2-amine

87 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-[3-(trifluoromethyl) phenyl]propanamide

88 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[3- (trifluoromethyl)phenyl]acetamide

89 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-{[3-(trifluoromethyl) phenyl]methyl}glycinamide

90 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-(2-phenylethyl)glycinamide

91 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-{2-[3-(trifluoromethyl) phenyl]ethyl}glycinamide

92 benzyl-{[5-chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)-pyridin-3-ylcarbamoyl]- methyl}-carbamic acid tert- butyl ester

93 N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N2-(phenylmethyl) glycinamide

94 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-3-[3,5- bis(trifluoromethyl) phenylacetamide

95 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-1,3-benzothiazol-2-yl)-2-[2- chloro-5-(trifluoromethyl) phenyl]acetamide

96 N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4-yl)methyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide

97 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(1,2,3,4- tetrahydroisoquinolin-1- ylmethyl)ethanediamide

98 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-[(2-methyl-1,2,3,4- tetrahydroisoquinolin-1- yl)methyl]ethanediamide

99 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-methyl-N2-{[3- (trifluoromethyl)phenyl]methyl}glycinamide

100 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-methyl-N2-{2-[3- (trifluoromethyl)phenyl]ethyl}glycinamide

101 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N2-methyl-N2-(2- phenylethyl)glycinamide

102 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-4-(phenylmethyl)imidazolidin- 2-one

103 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}pyridazin-3-yl)-N′-(4-fluorophenyl)propanediamide

104 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(2-chlorophenyl) propanediamide

105 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(3-chlorophenyl) propanediamide

106 N1-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N2-methyl-N2- (phenylmethyl)glycinamide

107 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(4-chlorophenyl) propanediamide

108 (2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2-[(methyloxy)imino] propanamide

109 (2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2-[(ethyloxy)imino]propanamide

110 (2E)-N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-2-{[(phenylmethyl)oxy]imino} propanamide

111 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-1-(phenylmethyl)prolinamide

112 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-3-[(4-methylphenyl)sulfonyl]-4- (phenylmethyl)imidazolidin- 2-one

113 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4-(phenylmethyl)imidazolidin- 2-one

114 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4-(phenylmethyl)-4,5-dihydro- 1,3-oxidiazol-2-amine

115 6,7-bis(methyloxy)-4-({4-[4- (phenylmethyl)piperazin-1-yl]phenyl}oxy)quinoline

116 1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-4-(phenylmethyl)piperazin-2- one

117 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2-(phenylmethyl)alaninamide

118 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2-methyl-N2-(phenylmethyl) alaninamide

119 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2-(phenylmethyl)leucinamide

120 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2-methyl-N2-(phenylmethyl) leucinamide

121 N1-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N2-(phenylmethyl)valinamide

122 4-(6,7-dimethoxy-quinolin-4- ylamino)-N-(3-phenyl- propyl)-benzamide

123 4-benzyl-1-[4-(6,7- dimethoxy-quinolin-4-yloxy)-phenyl]-tetrahydro-pyrimidin- 2-one

124 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide

125 2-(Benzyl-methyl-amino)-N- [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-methyl- butyramide (note: Alphabetic order of prefixesignored while selecting parent chain)

126 N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-phenyl]-2-phenoxyimino-propionamide

127 2-Benzyloxyimino-N-[4-(6,7- dimethoxy-quinolin-4-yloxy)-phenyl]-2-phenyl-acetamide

128 4-[4-(4-Benzyl-piperidin-1- yl)-phenoxy]-6,7-dimethoxy- quinoline

129 N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-isopropyl- 1,2,3,4-tetrahydro- isoquinolin-1-ylmethyl)-oxalamide

130 N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-ethyl-1,2,3,4- tetrahydro-isoquinolin-1-ylmethyl)-oxalamide

131 4-(4-{3-Chloro-5-[2-(4- fluoro-phenylcarbamoyl)-acetylamino]-pyridin-2- yloxy}-6-methoxy-quinolin-7-yloxymethyl)-piperidine-1- carboxylic acid tert-butyl ester

132 N-{5-Chloro-6-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-pyridin-3- yl}-N′-(4-fluoro-phenyl)- malonamide

133 N-{5-Chloro-6-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide

134 N-{4-[7-(3-Diethylamino- propoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-N′-phenethyl- oxalamide

135 N-{3-Fluoro-4-[6-methoxy-7- (3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide

136 N-{3-Fluoro-4-[6-methoxy-7- (3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-N′- phenethyl-oxalamide

137 N-{4-[7-(2-Diethylamino- ethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro-phenyl}-N′- phenethyl-oxalamide

138 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-methyl-N′- phenethyl-oxalamide

139 N-{3-Fluoro-4-[6-methoxy-7- (2-methyl-octahydro-cyclopenta[c]pyrrol-5- ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl- oxalamide

140 N-{3-Fluoro-4-[6-methoxy-7- (2-methyl-octahydro-cyclopenta[c]pyrrol-5- ylmethoxy)-quinazolin-4-yloxy]-phenyl}-N′-phenethyl- oxalamide

141 2-(3,4-Dihydro-1H- isoquinolin-2-yl)-N-{3-fluoro-4-[6-methoxy-7-(1-methyl- piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2- oxo-acetamide

142 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2- oxo-2-(3-phenyl-pyrrolidin-1- yl)-acetamide

143 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2- oxo-2-(2-phenyl-morpholin-4- yl)-acetamide

144 N-(2-Dimethylamino-2- phenyl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

145 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-oxo-2-phenyl-ethyl)- oxalamide

146 N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-2,2-difluoro-N′- (4-fluoro-phenyl)-malonamide

147 N-Benzyl-N′-{3-fluoro-4-[6- methoxy-7-(1-methyl-piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

148 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(2-fluoro-phenyl)-ethyl]- oxalamide

149 N-[2-(3-Chloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

150 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(2-methoxy-phenyl)-ethyl]- oxalamide

151 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-pyridin-3-yl-ethyl)- oxalamide

152 N-Benzyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

153 N-[2-(2,5-Dimthoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

154 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(2-trifluoromethyl-phenyl)-ethyl]-oxalamide

155 N-[2-(2-Ethoxy-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

156 N-[2-(2,4-Dimethyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

157 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1S-phenyl-2-p-tolyl-ethyl)- oxalamide

158 N-[2-(4-Chloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

159 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamic acid

160 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(3-fluoro-phenyl)-ethyl]- oxalamide

161 N-[2-(2-Chloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]phenyl}-oxalamide

162 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(3-methoxy-phenyl)-ethyl]- oxalamide

163 N-(1,2-Diphenyl-ethyl)-N′-{3- fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

164 N-[2-(2,4-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

165 N-[2-(3,4-Dimethoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

166 N-[2-(4-Ethyl-phenyl)-ethyl]- N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

167 N-[2-(4-Ethoxy-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

168 N-[2-(4-Ethoxy-3-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

169 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(4-phenoxy-phenyl)-ethyl]- oxalamide

170 N-[2-(3-Ethoxy-4-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]phenyl}-oxalamide

171 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-pyridin-2-yl-ethyl)- oxalamide

172 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-pyridin-4-yl-ethyl)- oxalamide

173 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(4-fluoro-phenyl)-ethyl]- oxalamide

174 N-[2-(2-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

175 N-[2-(2-Chloro-6-fluoro- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

176 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2R-phenyl-propyl)-oxalamide

177 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- indan-1-yl-oxalamide

178 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-isobutyl- oxalamide

179 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(3-methyl- butyl)-oxalamide

180 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2R- phenyl-propyl)-oxalamide

181 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(2-phenyl- propyl)-oxalamide

182 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-indan-2-yl- oxalamide

183 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1R-phenyl-ethyl)-oxalamide

184 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1S-phenyl-ethyl)-oxalamide

185 N-[2-(3-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]phenyl}-oxalamaide

186 N-[2-(2,6-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

187 N-[2-(2,4-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

188 N-(2-Benzo[1,3]dioxol-5-yl- ethyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]phenyl}-oxalamide

189 N-[2-(3-Bromo-4-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

190 N-[2-(3,5-Dimethoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

191 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-o-tolyl-ethyl)-oxalamide

192 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-m-tolyl-ethyl)-oxalamide

193 N-[2-(3-Ethoxy-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

194 N-[2-(3,4-Dimethyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

195 N-[2-(2,5-Dimethyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]phenyl}-oxalamide

196 N-[2-(3-Chloro-4-propoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

197 N-[2-(4-Butoxy-3-chloro- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

198 N-[2-(4-tert-Butyl-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

199 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(4-sulfamoyl-phenyl)- ethyl]-oxalamide

200 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-oxalamide

201 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(3-hydroxy-4-methoxy-phenyl)-ethyl]-oxalamide

202 N-(2,4-Dichloro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

203 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (4-fluoro-2-trifluoromethyl-benzyl)-oxalamide

204 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1-p-tolyl-ethyl)-oxalamide

205 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-fluoro-4-trifluoromethyl-benzyl)-oxalamide

206 N-(3-Chloro-4-fluoro-benzyl)- N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

207 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [1-(3-methoxy-phenyl)-ethyl]- oxalamide

208 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1-naphthalen-2-yl-ethyl)- oxalamide

209 N-(4-Chloro-3- trifluoromethyl-benzyl)-N′-{3-fluoro-4-[(6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide

210 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1-p-tolyl-ethyl)-oxalamide

211 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (6-trifluoromethyl-piperidin-3-ylmethyl)-oxalamide

212 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-methyl-benzyl)-oxalamide

213 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-methyl-benzyl)-oxalamide

214 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (4-fluoro-3-trifluoromethyl-benzyl)-oxalamide

215 N-(3,5-Dichloro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

216 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1R,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide

217 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1S,2,3,4-tetrahydro-naphthalen-1-yl)-oxalamide

218 N-Cyclopentyl-N′-{3-fluoro- 4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

219 N-[1-(4-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

220 N-(2-Fluoro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7-(piperidin-4-ylmethyl)- quinolin-4-yloxy]-phenyl}- oxalamide

221 N-[2-(3,4-Dichloro-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

222 N-(4-Fluoro-benzyl)-N′-{3- fluorro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

223 N-(2,3-Dichloro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

224 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-phenoxy-ethyl)-oxalamide

225 N-(2,2-Diphenyl-ethyl)-N′-{3- fluoro-4-[6-methoxy-7-(piepridin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

226 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [2-(4-methoxy-phenyl)-ethyl]- oxalamide

227 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-phenyl-propyl)-oxalamide

228 N-[2-(4-Bromo-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

229 N-{4-[7-(1-Ethyl-piperidin-4- ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-2-oxo-2-(2-phenyl-morpholin-4-yl)-acetamide

230 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-fluoro-5-trifluoromethyl-benzyl)-oxalamide

231 N-(3,5-Difluoro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

232 N-(2-Chloro-5- trifluoromethyl-benzyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

233 N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-3-fluoro-phenyl]-N′-(2-dimethylamino- 2-phenyl-ethyl)-oxalamide

234 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (4-methoxy-benzyl)- oxalamide

235 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (4-trifluoromethyl-benzyl)- oxalamide

236 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-methoxy-benzyl)- oxalamide

237 N-{3-Fluorro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-trifluoromethyl-benzyl)- oxalamide

238 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-trifluoromethoxy-benzyl)- oxalamide

239 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-methoxy-benzyl)- oxalamide

240 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-trifluoromethyl-benzyl)- oxalamide

241 N-(3-Chloro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

242 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]phenyl}-N′- (2-trifluoromethoxy-benzyl)- oxalamide

243 N-(2-Chloro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

244 N-{3-Fluoro-4-[6-methoxy-7- (piepridin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (4-trifluoromethoxy-benzyl)- oxalamide

245 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4- methoxy-benzyl)-oxalamide

246 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-(4- trifluoromethyl-benzyl)-oxalamide

247 N-{4-[7-(Azetidin-3- ylmethoxy)-6-methoxy-quinolin-4-yloxy]-3-fluoro- phenyl}-N′-phenethyl- oxalamide

248 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-azetidin-3-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide

249 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-hydroxy-2-phenyl-ethyl)- oxalamide

250 N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(2,4-difluoro- phenyl)-oxalamide

251 N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(4-fluoro- phenyl)-N′-methyl- malonamide

252 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1R-phenyl-propyl)- oxalamide

253 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (1R-phenyl-propyl)- oxalamide

254 N-(3,4-Difluoro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

255 N-(2,6-Difluoro-benzyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

256 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-[2-(4- fluoro-phenyl)-ethyl]-oxalamide

257 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N′-phenyl- oxalamide

258 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-fluoro-phenyl)-oxalamide

259 N-(4-Chloro-3-fluoro- phenyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

260 N-(3,4-Dimethoxy-phenyl)- N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

261 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (3-methyl-butyl)-oxalamide

262 N-(3,3-Dimethyl-butyl)-N′- {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

263 N-{5-Chloro-6-[6-methoxy-7- (3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-pyridin-3- yl}-N′-(4-fluoro-phenyl)- malonamide

264 N-{5-Chloro-6-[6-methoxy-7- (3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-pyridin-3- yl}-N′-(4-fluoro-phenyl)- malonamide

265 N-{5-Chloro-6-[7-(3- diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]- pyridin-3-yl}-N′-(4-fluoro-phenyl)-malonamide

266 N-(4-Chloro-benzyl)-N′-{3- fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

267 N-(3,5-Dimethoxy-benzyl)- N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

268 N-(4-Butyl-benzyl)-N′-{3- fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

269 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-p-tolyl-ethyl)-oxalamide

270 N-(3,5-Bis-trifluoromethyl- benzyl)-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

271 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- pyrazin-2-ylmethyl-oxalamide

272 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- pyridin-2-ylmethyl-oxalamide

273 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}- N′-phenethyl-oxalamide

274 N-{3-Fluoro-4-[6-methoxy-7- (1-methyl-piperidin-4-ylmethoxy)-quinazolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide

275 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-fluoro-3-trifluoromethyl-benzyl)-oxalamide

276 N-[2-(2-Bromo-6-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

277 N-[2-(3,4-Dimethoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-N-methyl- oxalamide

278 N-[2-(5-Bromo-2-methoxy- phenyl)-ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4-yloxy]-phenyl}-oxalamide

279 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-fluoro-5-trifluoromethyl-benzyl)-oxalamide

280 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- [1-(4-fluoro-phenyl)-ethyl]- oxalamide

281 N-(1S-Benzyl-2-oxo-2 pyrrolidin-1-yl-ethyl)-N′-{3-fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}- oxalamide

282 N-{3-Fluoro-4-[6-methoxy-7- (octahydro- cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4- yloxy]-phenyl}-N′-phenethyl- oxalamide

283 N-[2-(4-Amino-phenyl)- ethyl]-N′-{3-fluoro-4-[6-methoxy-7-(piperidin-4- ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

284 2-(4-Benzyl-piperidin-1-yl)- N-{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}-2- oxo-acetamide

285 N-[4-(6,7-Dimethoxy- quinolin-4-yloxy)-phenyl]-N′-(4-fluoro-phenyl)-malonamide

286 N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(3-fluoro- phenyl)-malonamide

287 N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-phenyl- malonamide

288 N-[5-Chloro-6-(6,7- dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-N′-(4-fluoro- phenyl)-2,2-dimethyl- malonamide

289 N-Ethyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

290 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- isopropyl-oxalamide

291 N-Butyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-oxalamide

292 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-methoxy-ethyl)-oxalamide

293 N-Cyclopropylmethyl-N′-{3- fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)- quinolin-4-yloxy]-phenyl}- oxalamide

294 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′- (2-morpholin-4-yl-ethyl)- oxalamide

295 N-{3-Fluoro-4-[6-methoxy-7- (piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-2- oxo-2-pyrrolidin-1-yl- acetamide

296 N-Ethyl-N′-{3-fluoro-4-[6- methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4- yloxy]-phenyl}-N-methyl- oxalamide

In another aspect, the invention comprises a compound for modulatingkinase activity of formula A-B-C, or a pharmaceutically acceptable salt,hydrate, or prodrug thereof, wherein, A is selected from:

B is selected from:

and, C is selected from:

wherein R² is selected from —H, halogen, trihalomethyl, —CN, —NH₂, —NO₂,—OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally substituted loweralkyl;q is 0 to 2;each R³ is independently selected from —H, optionally substituted loweralkyl, optionally substituted aryl, optionally substituted arylalkyl,and optionally substituted heteroarylalkyl; two R³, together with thenitrogen to which they are attached, form a four- to seven-memberedheteroalicyclic, said four- to seven-membered heteroalicyclic optionallycontaining one additional heteroatom; when one said additionalheteroatom is a nitrogen, then said nitrogen is optionally substitutedwith a group selected from —H, trihalomethyl, —SO₂R⁵, —SO₂NR⁵R⁵, —CO₂R⁵,—C(O)NR⁵R⁵, —C(O)R⁵, and optionally substituted lower alkyl;each R³⁵ is independently selected from —H, —C(═O)R³, —C(═O)OR³,—C(═O)SR³, —SO₂R³, —C(═O)N(R³)R³, and optionally substituted loweralkyl;two R³⁵, together with the nitrogen to which they are attached, cancombine to form a heteroalicyclic optionally substituted with betweenone and four of R⁶⁰, said heteroalicyclic may have an additional annularheteroatom, and said heteroalicyclic may have an aryl fused thereto,said aryl optionally substituted with an additional one to four of R⁶⁰;A¹ is selected from ═N—, ═C(H)—, and ═C(CN)—;A² is either ═N— or ═C(H)—;R⁵ is —H or optionally substituted lower alkyl;R⁸ is selected from R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —SO₂R³, and—C(O)R³;R⁹, R¹⁰, and R¹¹ are each independently selected from —H, and —OR¹²; orR⁹ is selected from —H, and —OR¹², and R¹⁰ and R¹¹, when taken together,are either an optionally substituted alkylidene or an oxo; andR¹² is selected from —H, —C(O)R³, optionally substituted loweralkylidyne, optionally substituted lower arylalkylidyne, optionallysubstituted lower heterocyclylalkylidyne, optionally substituted loweralkylidene, optionally substituted lower alkylidenearyl, optionallysubstituted lower alkylideneheterocyclyl, optionally substituted loweralkyl, optionally substituted lower alkylaryl, optionally substitutedaryl, optionally substituted lower heterocyclylalkyl, and optionallysubstituted heterocyclyl;or two R¹²'s, when taken together, form 1) a corresponding spirocyclicketal when said two R¹²'s stem from R¹⁰ and R¹¹, or 2) a correspondingcyclic ketal when said two R¹²'s stem from R⁹ and one of R¹⁰ and R¹¹;E¹ is selected from —O—, —CH₂—, —N(R⁵)—, and —S(O)₀₋₂—;Q is a five- to ten-membered ring system, optionally substituted withbetween zero and four of R²⁰;R²⁰ is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³,—NR³R³, —S(O)₀₋₂R, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally substituted loweralkyl;R⁶⁰ is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³,—NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted heteroarylalkyl, andoptionally substituted arylalkyl;two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo;each methylene in any of the above formulae is independently optionallysubstituted with R²⁵;each R²⁵ is independently selected from halogen, trihalomethyl, —CN,—NO₂, —NH₂, —OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substitutedaryl, optionally substituted arylalkyl, heteroarylalkyl, and optionallysubstituted lower alkyl; two of R²⁵, together with the carbon or carbonsto which they are attached, can combine to form a three- toseven-membered alicyclic or heteroalicyclic, two of R²⁵ on a singlecarbon can be oxo;with the proviso that when B is selected from:

and C contains

and the remaining portion of C contains one of:

directly attached to

then A must be one of:

and with the proviso that when C contains

and B is selected from:

then the portion of C directly attached to

cannot contain

when R⁷⁰ is selected from —H, C₁₋₄alkyl, and C₁₋₄alkoxyl.

In another example the compound is according to the preceding paragraph,wherein Q is selected from phenyl, napthyl, 1,2,3,4-tetrahydronaphthyl,indanyl, benzodioxanyl, benzofuranyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroisoquinolyl, pyrrolyl, pyrazolyl, pyrazolidinyl,imidazolyl, imidazolinyl, imidazolidinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, thiazolyl,thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl, quinolyl, isoquinolyl, benzimidazolyl,thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl,thienyl, benzothieliyl, and oxadiazolyl; each optionally substitutedwith between one and four of R²⁰; wherein each R²⁰ is independentlyselected from —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³, —NR³R³,—CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, andoptionally substituted lower alkyl.

In another example the compound is according to the preceding paragraph,wherein B is either of the following:

wherein A¹ is either ═N— or ═C(H)—.

In another example the compound is according to the preceding paragraph,wherein B is

In another example the compound is according to the preceding paragraph,wherein C is selected from:

wherein R², R³, R⁵, R²⁰, R²⁵ and R⁶⁰ are as defined above.

In another example the compound is according to the preceding paragraph,R² is selected from halogen, trihalomethyl, —CN, —NO₂, —OR³, —NR³R³,—CO₂R³, —C(O)NR³R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionallysubstituted lower alkyl

In another example the compound is according to the preceding paragraph,wherein R² is halogen.

In another example the compound is according to the preceding paragraph,wherein R² is either fluorine or chlorine.

In another aspect, the invention comprises a compound for modulatingkinase activity according to Formula XI,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,wherein,each R¹ is independently selected from halogen, —OR³, —NO₂, —NH₂,—NR³R⁴, -D-R⁵, and optionally substituted C₁₋₆alkyl;R⁷⁰ is selected from —H, halogen, —OR³, —S(O)₀₋₂R³, —NO₂, —NH₂, —NR³R⁴,and optionally substituted C₁₋₆alkyl;Q is selected from ═N—, ═C(H)—, and ═C(CN)—;Z is selected from —S(O)₀₋₂—, —O—, and —NR⁵—;Ar is either a five- or six-membered arylene or a five- or six-memberedheteroarylene containing between one and three heteroatoms;G is either an optionally substituted cycloalkyl or an optionallysubstituted heteroalicyclic;each R² is independently selected from halogen, trihalomethyl, —CN,—NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionallysubstituted C₁₋₆alkyl;each R³ is independently —H or R⁴;each R⁴ is independently selected from optionally substituted C₁₋₆alkyl,optionally substituted aryl, optionally substituted aryl C₁₋₆alkyl,optionally substituted heterocyclyl, and optionally substitutedheterocyclyl C₁₋₆alkyl; orR³ and R⁴, when taken together with a common nitrogen to which they areattached, form an optionally substituted five- to seven-memberedheterocyclyl, said optionally substituted five- to seven-memberedheterocyclyl optionally containing at least one additional annularheteroatom selected from N, O, S, and P;R⁵ is —H or optionally substituted C₁₋₆alkyl;each D is independently selected from —O—, —S(O)₀₋₂—, and —NR⁵—;each R⁵⁰ is independently either R³, or according to formula XII;

wherein X¹, X², and optionally X³, represent the atoms of a saturatedbridged ring system, said saturated bridged ring system comprising up tofour annular heteroatoms represented by any of X¹, X², and X³; wherein,

-   -   each X¹ is independently selected from —C(R⁶)R⁷—, —O—,        —S(O)₀₋₂—, and —NR⁸—;    -   each X² is independently an optionally substituted bridgehead        methine or a bridgehead nitrogen;    -   each X³ is independently selected from —C(R⁶)R⁷—, —O—,        —S(O)₀₋₂—, and —NR⁸—;        Y is either:    -   an optionally substituted lower alkylene linker, between D and        either 1) any annular atom of the saturated bridged ring system,        except X² when X² is a bridgehead nitrogen, or 2) any        heteroatom, represented by any of R⁶ or R⁷; provided there are        at least two carbon atoms between D and any annular heteroatom        of the saturated bridged ring system or any heteroatom        represented by any of R⁶ or R⁷;    -   or Y is absent, when Y is absent, said saturated bridged ring        system, is directly attached to D via an annular carbon of said        saturated bridged ring system, unless D is —SO₂—, in which case        said saturated bridged ring system, is directly attached to D        via an any annular atom of said saturated bridged ring system;        m and p are each independently one to four;        n is zero to two, when n equals zero, then there is a single        bond between the two bridgehead X²'s;        R⁶ and R⁷ are each independently selected from —H, halogen,        trihalomethyl, —CN, —NH₂, —NO₂, —OR³, —NR³R⁴, —S(O)₀₋₂R⁴,        —SO₂NR³R⁴, —CO₂R³, —C(O)NR³R⁴, —N(R³)SO₂R⁴, —N(R³)C(O)R³,        —NCO₂R³, —C(O)R³, optionally substituted C₁₋₆alkyl, optionally        substituted aryl, optionally substituted aryl C₁₋₆alkyl,        optionally substituted heterocyclyl, optionally substituted        heterocyclyl C₁₋₆alkyl, and a bond to either Y or D; or        R⁶ and R⁷, when taken together are oxo; or        R⁶ and R⁷, when taken together with a common carbon to which        they are attached, form a optionally substituted three- to        seven-membered spirocyclyl, said optionally substituted three-        to seven-membered spirocyclyl optionally containing at least one        additional annular heteroatom selected from N, O, S, and P;        R⁸ is selected from —R³, Y, —SO₂NR³R⁴, —CO₂R⁴, —C(O)NR³R³,        —SO₂R⁴, and —C(O)R³; and        each R³⁰ is independently selected from halogen, trihalomethyl,        —CN, —NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³,        —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and        optionally substituted C₁₋₆alkyl.

In one example, the compound is according to Formula XI, wherein Z iseither —O— or —NR⁵—.

In another example, the compound is according to the precedingparagraph, wherein at least one of R¹ is -D-R⁵⁰.

In another example, the compound is according to the precedingparagraph, wherein D is —O— and at least one other R¹ is —OR³.

In another example, the compound is according to the precedingparagraph, of formula XIIIa or XIIIb:

wherein Q¹ is either ═N— or ═C(H)—.

In another example, the compound is according to formula XIIIa orformula XIIIb, wherein R⁵⁰ is selected from C₁₋₆alkyl optionallysubstituted with at least one of optionally substituted amino,optionally substituted C₁₋₆alkyl amino, optionally substitutedC₁₋₆dialkyl amino, optionally substituted heteroalicylic, and a group offormula XII.

In another example, the compound is according to the precedingparagraph, wherein R^(3a) is C₁₋₆alkyl.

In another example, the compound is according to the precedingparagraph, wherein Z is —O—.

In another example, the compound is according to the precedingparagraph, wherein G is selected from cyclopropyl, aziradine,cyclobutyl, and azetidine, each optionally substituted with between zeroand four of R³⁰.

In another example, the compound is according to the precedingparagraph, wherein Q is either ═N— or ═C(H)—.

In another example, the compound is according to the precedingparagraph, wherein R² is selected from —H, halogen, C₁₋₆ alkyl andperfluoro C₁₋₆ alkyl.

In another example, the compound is according to the precedingparagraph, wherein —N(R^(3b))R⁴ is selected from the following:

wherein J, is a five- to ten-membered ring, optionally substituted withbetween zero and five of R²⁰;each R²⁰ is independently selected from —H, halogen, trihalomethyl, —CN,—NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substitutedC₁₋₆alkyl, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, optionally substituted heterocyclyl, and optionallysubstituted heterocyclyl C₁₋₆alkyl;two of R²⁰, together with the atom or atoms to which they are attached,combine to form an optionally substituted three- to seven-memberedheteroalicyclic, said optionally substituted three- to seven-memberedheteroalicyclic either spiro- to J or fused to J;E is selected from —O—, —N(R⁵)—, —CH₂—, and —S(O)₀₋₂—;each R⁶⁰ is independently selected from halogen, trihalomethyl, —CN,—NO₂, —NH₂, —OR³, —NR³R⁴, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substitutedC₁₋₆alkyl, optionally substituted aryl, optionally substitutedheteroaryl C₁₋₆alkyl, and optionally substituted aryl C₁₋₆alkyl;each methylene in any of the above formulae, other than those in adepicted ring, is independently optionally substituted with R²⁵; andR²⁵ is selected from halogen, trihalomethyl, oxo, —CN, —NO₂, —NH₂, —OR³,—NR³R⁴, —S(O)₀₋₂R³—SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substituted aryl,optionally substituted aryl C₁₋₆alkyl, heteroaryl C₁₋₆alkyl, andoptionally substituted C₁₋₆alkyl; ortwo of R²⁵, together with the carbon or carbons to which they areattached, can combine to form a three- to seven-membered alicyclic orheteroalicyclic;R^(3b) is equivalent to R³ as defined above; andR⁴ and R⁵ are as defined above.

In another example, the compound is according to the precedingparagraph, of formula XIVa or XIVb:

In another example, the compound is according to the precedingparagraph, wherein R⁵⁰ is C₁₋₆alkyl optionally substituted with a groupselected from optionally substituted amino, an optionally substitutedalkylamino, optionally substituted dialkylamino, and optionallysubstituted heteroalicylic.

In another example, the compound is according to the precedingparagraph, wherein the heteroalicyclic portion of R⁵⁰ is selected fromthe group consisting of piperidine, piperazine, morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,2-oxo-morpholine, pyrrolidine, and azepine.

In another example, the compound is as defined two paragraphs above,wherein R⁵⁰ is according to formula XII.

In another example, the compound is according to the precedingparagraph, wherein the saturated bridged ring system according toformula XII has a geometry selected from the group consisting of[4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3],[3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1].

In another example, the compound is according to the precedingparagraph, wherein Y is selected from —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂—, —CH₂—, and absent.

In another example, the compound is according to the precedingparagraph, wherein n is 0 and the saturated bridged ring systemaccording to formula XII has a geometry selected from the groupconsisting of [4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], and[3.1.0].

In another example, the compound is according to the precedingparagraph, wherein said saturated bridged ring system contains at leastone annular nitrogen or at least one annular oxygen.

In another example, the compound is according to the precedingparagraph, wherein said saturated bridged ring system contains —NR⁸—,wherein R⁸ is selected from —H, optionally substituted C₁₋₆alkyl,—CO₂R³, —C(O)NR³R³, —SO₂R³, and —C(O)R³.

In another example, the compound is as defined two paragraphs above,wherein said saturated bridged ring system is of formula XV,

wherein U¹ is selected from —O—, —S(O)₀₋₂—, —NR⁸—, —CR⁶R⁷—, and absent;and e is 0 or 1.

In another example, the compound is according to the precedingparagraph, wherein Y is —CH₂—.

In another example, the compound is according to the precedingparagraph, wherein U¹ is —NR⁸—, wherein R⁸ is selected from —H,optionally substituted lower alkyl, —CO₂R³, —C(O)NR³R³, —SO₂R³, and—C(O)R³.

In another example, the compound is as defined two paragraphs above,wherein U¹ is —O—.

In another example, the compound is as defined three paragraphs above,wherein U¹ is absent.

In another example, the saturated bridged ring system is according toformula XII and has a geometry selected from the group consisting of[4.4.0], [4.3.0], [4.2.0], [4.1.0], [3.3.0], [3.2.0], [3.1.0], [3.3.3],[3.3.2], [3.3.1], [3.2.2], [3.2.1], [2.2.2], and [2.2.1], and Y isselected from —CH₂CH₂—, —CH₂—, and absent.

In another example, the compound is according to the precedingparagraph, wherein said saturated bridged ring system is of formula XVI,

wherein R⁹, R¹⁰, and R¹¹ are each independently selected from —H, and—OR¹²; orR⁹ is selected from —H, and —OR², and R¹⁰ and R¹¹, when taken together,are either an optionally substituted alkylidene or an oxo;R¹² is selected from —H, —C(O)R³, optionally substituted loweralkylidyne, optionally substituted lower arylalkylidyne, optionallysubstituted lower heterocyclylalkylidyne, optionally substituted loweralkylidene, optionally substituted lower alkylidenearyl, optionallysubstituted lower alkylideneheterocyclyl, optionally substituted loweralkyl, optionally substituted lower alkylaryl, optionally substitutedaryl, optionally substituted lower heterocyclylalkyl, and optionallysubstituted heterocyclyl;or two R¹²'s, when taken together, form 1) a corresponding spirocyclicketal when said two R¹²'s stem from R¹⁰ and R¹¹, or 2) a correspondingcyclic ketal when said two R¹²'s stem from R⁹ and one of R¹⁰ and R¹¹.

In another example, the compound is according to the precedingparagraph, wherein one of R¹⁰ and R¹¹ is —OR¹², wherein R¹² is selectedfrom —H, —C(O)R³, and optionally substituted lower alkyl; and R⁹ and theother of R¹⁰ and R¹¹ are both —H.

In another example, the compound is according to the precedingparagraph, wherein Y is either —CH₂— or absent.

In another example, the compound is as defined three paragraphs above,wherein R⁹ is an alkyl group containing at least one fluorinesubstitution thereon.

In another example, the compound is as defined eleven paragraphs above,wherein said saturated bridged ring system is of formula XVII, whereinR⁸ is selected from —H, optionally substituted C₁₋₆alkyl, —CO₂R³,—C(O)NR³R³, —SO₂R³, and —C(O)R³.

In another example, the compound is according to the precedingparagraph, wherein Y is either —CH₂— or absent.

In another example, the compound is according to the precedingparagraph, wherein R⁸ is methyl or ethyl.

In another example, the compound is according to the precedingparagraph, wherein at least one of R² is halogen.

In another example, the compound is as defined fifteen paragraphs above,wherein said saturated bridged ring system is of formula XVIII, whereinR⁸ is selected from —H, optionally substituted C₁₋₆alkyl, —CO₂R³,—C(O)NR³R³, —SO₂R³, and —C(O)R³.

In another example, the compound is according to the precedingparagraph, wherein Y is —CH₂—.

In another example, the compound is according to the precedingparagraph, wherein R⁸ is methyl or ethyl.

In another example, the compound is as defined nineteen paragraphsabove, wherein said saturated bridged ring system is of formula XIX

wherein U² is selected from —O—, —S(O)₀₋₂—, —NR⁸—, —CR⁶R⁷—, and absent.

In another example, the compound is according to the precedingparagraph, wherein R³ of formula XIX is selected from —H and optionallysubstituted alkyl.

In another example, the compound is according to the precedingparagraph, wherein U² is either —CR⁶R⁷— or absent.

In another example, the compound is according to the precedingparagraph, wherein U² is either —CH₂— or absent.

In another example, the compound is according to the precedingparagraph, wherein Y is —CH₂—.

In another example, the compound is as defined above, wherein saidsaturated bridged ring system is according to formula XX, wherein R⁸ isselected from —H, optionally substituted C₁₋₆alkyl, —CO₂R³, —C(O)NR³R³,—SO₂R³, and —C(O)R³.

In another example, the compound is according to the precedingparagraph, wherein R⁸ is methyl or ethyl.

In another example, the compound is according to formula XIVa or XIVb,wherein R² is selected from C₁₋₆ alkyl, perfluoro C₁₋₆ alkyl, andhalogen.

In another example, the compound is according to the precedingparagraph, wherein R² is selected from perfluoro C₁₋₃ alkyl and halogen.

In another example, the compound is according to formula XIVa or XIVb,wherein R²⁰ is selected from halogen, —CN, —NO₂, —NH₂, —OR³, —NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, optionally substitutedheterocyclyl, and optionally substituted heterocyclyl C₁₋₆alkyl, and(two of R²⁰) together with the atom or atoms to which they are attached,an optionally substituted three- to six-membered heteroalicyclic, saidoptionally substituted three- to six-membered heteroalicyclic fused tothe phenyl as in XIVa or XIVb.

In another example, the compound is according to the precedingparagraph, wherein R²⁰ is selected from halogen, —NR³R⁴, optionallysubstituted heterocyclyl, and optionally substituted heterocyclylC₁₋₆alkyl, and (two of R²⁰) together with the atom or atoms to whichthey are attached, an optionally substituted five- to six-memberedheteroalicyclic, said optionally substituted five- to six-memberedheteroalicyclic fused to the phenyl as in XIVa or XIVb.

In another example, the compound is according to the precedingparagraph, wherein R² is selected from C₁₋₆ alkyl, perfluoro C₁₋₆ alkyl,and halogen.

In another example, the compound is according to the precedingparagraph, wherein R² is selected from perfluoro C₁₋₃ alkyl and halogen.

In another example, the compound is selected from Table 2.

TABLE 2 Entry Name Structure 1 N-(6-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin- 3-yl)-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide

2 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(4-fluorophenyl) cyclobutane-1,1- dicarboxamide

3 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(phenylmethyl) cyclopropane-1,1- dicarboxamide

4 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′- phenylcyclopropane-1,1- dicarboxamide

5 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy) phenyl]-N′-(4- fluorophenyl) cyclopropane-1,1-dicarboxamide

6 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1-ylpropyl)oxy]quinolin-4-yl}oxy) phenyl]-N′-(4- fluorophenyl) cyclopropane-1,1-dicarboxamide

7 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperidin-1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide

8 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin-3-yl)-N′-(2-phenylethyl) cyclopropane-1,1- dicarboxamide

9 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylpyridin-3-yl)-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

10 N-{4-[(7-chloroquinolin- 4-yl)oxy]-3- fluorophenyl}-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

11 N-{4-[(7-chloroquinolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

12 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

13 N-(6-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

14 N-(6-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}-3-fluorophenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

15 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- cyclopropane-1,1-dicarboxamide

16 N-{5-chloro-6-[(6- (methyloxy)-7-{[(1- methylpiperidin-4-yl)methyl]oxy}quinolin- 4-yl)oxy]pyridin-3-yl}- N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide

17 N-[5-chloro-6-({6- (methyloxy)-7- [(piperidin-4-ylmethyl)oxy]quinolin-4- yl}oxy)pyridin-3-yl]-N′- (4-fluorophenyl)cyclopropane-1,1- dicarboxamide

18 N-[5-chloro-6-({6- (methyloxy)-7- [(phenylmethyl)oxy]quino-lin-4-yl}oxy)pyridin-3- yl]-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide

19 N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide

20 N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl) cyclobutane-1,1-dicarboxamide

21 N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4-yl)methyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

22 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylphenyl)-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

23 N-(4-fluorophenyl)-N′-[2- methyl-6-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)pyridin-3-yl]cyclopropane-1,1- dicarboxamide

24 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

25 N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloro-2-methylpyridin-3-yl)-N′- (4-fluorophenyl) cyclopropane-1,1- dicarboxamide

26 N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide

27 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3,5-difluorophenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

28 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,5-difluorophenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

29 N-[3-fluoro-4-({7- (methyloxy)-6-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

30 N-{3-fluoro-4-[(6- (methyloxy)-7-(2-methyl octahydrocyclo-penta[c]pyrrol-5- ylmethoxy)quinazolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

31 N-{3-fluoro-4-[(7- (methyloxy)-6-{[(1- methylpiperidin-4-yl)methyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

32 N-[5-fluoro-2-methyl-4- ({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

33 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,3,5-trifluorophenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

34 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-2-methylphenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

35 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5-methylphenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

36 N-(3-fluoro-4-{[6- hydroxy-7- (methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

37 N-(4-fluorophenyl)-N′-[2- methyl-4-({6- (methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4- yl}oxy)phenyl] cyclopropane-1,1-dicarboxamide

38 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

39 N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

40 N-{3-fluoro-4-[(6- (methyloxy)-7-{[(1- methylpiperidin-4-yl)methyl]oxy}quinolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

41 N-(4-fluorophenyl)-N′-[4- ({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl] cyclopropane-1,1- dicarboxamide

42 N-(4-{[7-{[3- (diethylamino)propyl]oxy}- 6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl) cyclopropane-1,1-dicarboxamide

43 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5-fluorophenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

44 N-(4-{[6,7- bis(methyloxy)-2- (methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide

45 N-(4-fluorophenyl)-N′-(4- {[2-methyl-6,7- bis(methyloxy)quinazolin-4-yl]oxy}phenyl) cyclopropane-1,1- dicarboxamide

46 N-(4-{[2-amino-6,7- bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide

47 N-(3-fluoro-4-{[2- (methylamino)-6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4- fluorophenyl) cyclopropane-1,1- dicarboxamide

48 (1S,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

49 (1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

50 N-(4-{[6-{[3- (diethylamino)propyl]oxy}- 7-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl) cyclopropane-1,1-dicarboxamide

51 N-(4-{[6-{[2- (diethylamino)ethyl]oxy}- 7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide

52 1,1-dimethylethyl 4-(3- {[4-[(2-fluoro-4-{[(1- {[(4-fluorophenyl)amino]carbonyl}cyclopro- pyl)carbonyl]amino}phenyl) oxy]-6-(methyloxy)quinolin-7-yl]oxy}propyl) piperazine-1-carboxylate

53 (1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

54 (1R,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2- methylcyclopropane-1,1- dicarboxamide

55 N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

56 N-(4-{[7-{[3-(4- acetylpiperazin-1- yl)propyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide

57 1,1-dimethylethyl 4-(3- {[4-[(2-fluoro-4- {[((1R,2R)-1-{[(4-fluorophenyl)amino] carbonyl}-2- methylcyclopropyl)carbonyl]amino}phenyl)oxy]-6- (methyloxy)quinolin-7- yl]oxy}propyl)piperazine-1-carboxylate

58 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4-fluorophenyl)-1- (phenylmethyl)azetidine- 3,3-dicarboxamide

59 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4-fluorophenyl)azetidine- 3,3-dicarboxamide

60 (1R,2S)-N-{3-fluoro-4- [(6-(methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

61 (1R,2R)-N-{3-fluoro 4- [(6-(methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

62 (1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- piperazin-1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

63 N-(3-fluoro-4-{[7-({3-[4- (1-methylethyl)piperazin-1-yl]propyl}oxy)-6- (methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4-fluorophenyl) cyclopropane-1,1- dicarboxamide

64 N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane-1,1- dicarboxamide

65 (1R,2R)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

66 (1R,2R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

67 (1R,2S)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

68 (1R,2S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

69 N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide

70 (1R,2S)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- piperazin-1-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

71 (1R,2R,3S)-N-[3-fluoro- 4-({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane- 1,1-dicarboxamide

72 (1R,2R,3S)-N-{3-fluoro- 4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1- yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

73 (1R,2R,3S)-N-[3-fluoro- 4-({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane- 1,1-dicarboxamide

74 (1R,2R,3S)-N-{3-fluoro- 4-[(6-(methyloxy)-7-{[3-(4-methylpiperazin-1- yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

75 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane- 1,1-dicarboxamide

76 (2R,3R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane- 1,1-dicarboxamide

77 (2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluoropheny1)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane- 1,1-dicarboxamide

78 N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2-dimethylcyclopropane- 1,1-dicarboxamide

79 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,2-dimethylcyclopropane- 1,1-dicarboxamide

80 (1R,2R,3S)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane- 1,1-dicarboxamide

81 N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)- N′-(4-fluorophenyl)-2,2- dimethylcyclopropane-1,1-dicarboxamide

82 (1R,2R,3S)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

83 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinolin-4- yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,2-dimethylcyclopropane- 1,1-dicarboxamide

84 N-(4-{[7-{[2- (diethylamino)ethyl]oxy}- 6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2-dimethylcyclopropane- 1,1-dicarboxamide

85 N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,2-dimethylcyclopropane- 1,1-dicarboxamide

86 N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide

87 N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane- 1,1-dicarboxamide

88 N-[3-fluoro-4-({6- (methyloxy)-7-[(3- piperazin-1-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane- 1,1-dicarboxamide

89 (2R,3R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- morpholin-4-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane- 1,1-dicarboxamide

90 N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclobutane-1,1-dicarboxamide

91 N-{3-fluoro-4-[(6- (methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane- 1,1-dicarboxamide

92 (1R,2R)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

93 (1R,2R)-N-{3-fluoro-4- [(6-(methyloxy)-7-{[3-(4- methylpiperazin-1-yl)propyl]oxy}quinazolin- 4-yl)oxy]phenyl}-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

94 (2R,3R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

95 (2R,3R)-N-(4-{[7-{[3- (diethylamino)propyl] oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)-2,3-dimethylcyclopropane- 1,1-dicarboxamide

96 (1R,2R)-N-[3-fluoro-4- ({6-(methyloxy)-7-[(3- piperazin-1-ylpropyl)oxy]quinazolin- 4-yl}oxy)phenyl]-N′-(4- fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide

97 (2R,3R)-N-(4-{[7-{[2- (diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3- dimethylcyclopropane- 1,1-dicarboxamide

98 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[(4-fluorophenyl)methyl] cyclopropane-1,1- dicarboxamide

99 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(2-morpholin-4-ylethyl) cyclopropane-1,1- dicarboxamide

100 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[2-(piperidin-1-ylmethyl) phenyl]cyclopropane-1,1- dicarboxamide

101 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[2-(pyrrolidin-1-ylmethyl) phenyl]cyclopropane-1,1- dicarboxamide

102 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[3-(morpholin-4-ylmethyl) phenyl]cyclopropane-1,1- dicarboxamide

103 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[2-(morpholin-4-ylmethyl) phenyl]cyclopropane-1,1- dicarboxamide

104 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-phenylcyclopropane-1,1- dicarboxamide

105 N-[3- (aminomethyl)phenyl]-N′- (4-{[6,7-bis(methyloxy)quinolrn-4-yl]oxy} phenyl)cyclopropane-1,1- dicarboxamide

106 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[3-(piperidin-1-ylmethyl) phenyl]cyclopropane-1,1- dicarboxamide

107 N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-[3-(pyrrolidin-1-ylmethyl) phenyl]cyclopropane-1,1- dicarboxamide

Another aspect of the invention is a pharmaceutical compositioncomprising a compound according to the invention and a pharmaceuticallyacceptable carrier.

Another aspect of the invention is a metabolite of the compound or thepharmaceutical composition according to the invention.

Another aspect of the invention is a method of modulating the in vivoactivity of a kinase, the method comprising administering to a subjectan effective amount of the compound or the pharmaceutical compositionaccording to the invention.

Another aspect of the invention is the method according to the precedingparagraph, wherein modulating the in vivo activity of the kinasecomprises inhibition of said kinase.

Another aspect of the invention is the method according to the precedingparagraph, wherein the kinase is at least one of c-Met, KDR, c-Kit,flt-3, and flt-4.

Another aspect of the invention is the method according to the precedingparagraph, wherein the kinase is c-Met.

Another aspect of the invention is a method of treating diseases ordisorders associated with uncontrolled, abnormal, and/or unwantedcellular activities, the method comprising administering, to a mammal inneed thereof, a therapeutically effective amount of the compound or thepharmaceutical composition as described herein.

Another aspect of the invention is a method of screening for a modulatorof a kinase, said kinase selected from c-Met, KDR, c-Kit, flt-3, andflt-4, the method comprising combining a compound according to theinvention, and at least one candidate agent and determining the effectof the candidate agent on the activity of said kinase.

Another aspect of the invention is a method of inhibiting proliferativeactivity in a cell, the method comprising administering an effectiveamount of a composition comprising a compound according to the inventionto a cell or a plurality of cells.

As mentioned, although improved quinolines and quinazolines of theinvention can be made via conventional serial methods, due to theircomplex structure, more efficient routes are desirable, particularlyconvergent syntheses. Thus, the present invention also comprises aprocess for preparing a compound of Formula XXI,

comprising reaction of a compound of Formula XXII, with a compound ofFormula XXIII

wherein,each R¹ is independently selected from halogen, —OR³, —NO₂, —NH₂,—NR³R³, -D-R⁵⁰ and optionally substituted C₁₋₆alkyl;R⁷⁰ is selected from —H, halogen, —OR³, —S(O)₀2R³, —NO₂, —NH₂, —NR³R³,and optionally substituted C₁₋₆alkyl;J is selected from ═N—, ═C(H)—, ═C(halogen)-, and ═C(CN)—;Z is selected from —S(O)₀₋₂—, —O—, and —NR⁵—;each R⁵ is independently selected from —H, optionally substitutedC₁₋₆alkyl, optionally substituted aryl, and optionally substituted arylC₁₋₆alkyl;Ar is either a five- to ten-membered arylene or a five- to ten-memberedheteroarylene containing between one and three heteroatoms;R² is selected from —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR³,—NR³R³, —S(O)₀₋₂R^(W), —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally substitutedC₁₋₆alkyl;each R³ is independently selected from —H, —Si(R⁵)(R⁵)R⁵, optionallysubstituted lower alkyl, optionally substituted aryl, optionallysubstituted arylalkyl, and optionally substituted heteroarylalkyl;two R³, together with the nitrogen to which they are attached, form afour- to seven-membered heteroalicyclic, said four- to seven-memberedheteroalicyclic optionally containing one additional heteroatom; whenone said additional heteroatom is a nitrogen, then said nitrogen isoptionally substituted with a group selected from —H, trihalomethyl,—SO₂R⁵, —SO₂NR⁵R⁵, —CO₂R⁵, —C(O)NR⁵R⁵, —C(O)R⁵, and optionallysubstituted lower alkyl;B is selected from absent, —N(R¹³)—, —N(SO₂R³)—, —O—, —S(O)₀₋₂—, and—C(═O)—;L is selected from absent, —C(═S)N(R¹³)—, —C(═NR¹⁴)N(R¹³)—, —SO₂N(R¹³)—,—SO₂—, —C(═O)N(R¹³)—, —N(R¹³)—, —C(═O)C₁₋₂alkylN(R¹³)—,—N(R¹³)C₁₋₂alkylC(═O)—, —C(═O)C₀₋₁alkylC(═O)N(R¹³)—, —C(═O)—,—C₀₋₄alkylene-, —C(═O)C₀₋₁alkylC(═O)OR³—, —C(═NR¹⁴)C₀₋₁alkylC(═O)—,—C(═O)C₀₋₁alkylC(═O)—, and an optionally substituted four- tosix-membered heterocyclyl containing between one and three annularheteroatoms and comprising at least one nitrogen;T is selected from —H, —R¹³, —C₀₋₄alkyl, —C₀₋₄alkylQ, —OC₀₋₄alkylQ,—C₀₋₄alkylOQ, —N(R¹³)C₀₋₄alkylQ, —SO₂C₀₋₄alkylQ, —C(═O)C₀₋₄alkylQ,—C₀₋₄alkylN(R¹³)Q, and —C(═O)N(R¹³)C₀₋₄alkylQ, wherein each of theaforementioned C₀₋₄alkyl is optionally substituted;Q is a five- to ten-membered ring system, optionally substituted withbetween zero and four of R²⁰;each R²⁰ is independently selected from —H, halogen, trihalomethyl, —CN,—NO₂, —NH₂, —OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substitutedC₁₋₆alkyl, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, optionally substituted heterocyclyl, and optionallysubstituted heterocyclyl C₁₋₆alkyl;two of R, together with the atom or atoms to which they are attached,combine to form an optionally substituted three- to seven-memberedheteroalicyclic, said optionally substituted three- to seven-memberedheteroalicyclic either spiro- to Q or fused to Q;D is selected from —O—, —S(O)₀₋₂—, and —NR¹⁵—;R⁵⁰ is either R³, or according to formula XXIV;

wherein X¹, X², and optionally X³, represent the atoms of a saturatedbridged ring system, said saturated bridged ring system comprising up tofour annular heteroatoms represented by any of X¹, X², and X³; wherein,

-   -   each X¹ is independently selected from —C(R⁶)R⁷—, —O—, —S(O)₀,        and —NR⁸—;    -   each X² is independently an optionally substituted bridgehead        methine or a bridgehead nitrogen;    -   each X³ is independently selected from —C(R⁶)R⁷—, —O—,        —S(O)₀₋₂—, and —NR⁸—;        Y is either:    -   an optionally substituted C₁₋₆alkylene linker, between D and        either 1) any annular atom of the saturated bridged ring system,        except X² when X² is a bridgehead nitrogen, or 2) any        heteroatom, represented by any of R⁶ or R⁷; provided there are        at least two carbon atoms between D and any annular heteroatom        of the saturated bridged ring system or any heteroatom        represented by any of R⁶ or R⁷;    -   or Y is absent, when Y is absent, said saturated bridged ring        system, is directly attached to D via an annular carbon of said        saturated bridged ring system, unless D is —SO₂—, in which case        said saturated bridged ring system, is directly attached to D        via an any annular atom of said saturated bridged ring system;        m and p are each independently one to four;        n is zero to two, when n is zero, then there is a single bond        between the two bridgehead X²'s;        R⁶ and R⁷ are each independently selected from —H, halogen,        trihalomethyl, —CN, —NH₂, —NO₂, —OR³, —NR³R³, —S(O)₀₋₂R³,        —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³,        —NCO₂R³, —C(O)R³, optionally substituted C₁₋₆alkyl, optionally        substituted aryl, optionally substituted aryl C₁₋₆alkyl,        optionally substituted heterocyclyl, optionally substituted        heterocyclyl a C₁₋₆alkyl, and a bond to either Y or D; or        R⁶ and R⁷, when taken together are oxo; or        R⁶ and R⁷, when taken together with a common carbon to which        they are attached, form a optionally substituted three- to        seven-membered spirocyclyl, said optionally substituted three-        to seven-membered spirocyclyl optionally containing at least one        additional annular heteroatom selected from N, O, S, and P;        R⁸ is selected from —R³, Y, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,        —SO₂R³, and —C(O)R³;        R¹³ is selected from —H, —C(═O)R³, —C(═O)OR³, —C(═O)SR³, —SO₂R³,        —C(═O)N(R³)R³, and optionally substituted C₁₋₆alkyl;        two R¹³, together with the atom or atoms to which they are        attached, can combine to form a heteroalicyclic optionally        substituted with between one and four of R⁶⁰, said        heteroalicyclic comprising up to four annular heteroatoms, and        said heteroalicyclic optionally comprising an aryl or heteroaryl        fused thereto, in which case said aryl or heteroaryl is        optionally substituted with an additional one to four of R⁶⁰;        R¹⁴ is selected from —H, —NO₂, —NH₂, —N(R³)R³, —CN, —OR³,        optionally substituted C₁₋₆alkyl, optionally substituted        heteroalicyclyl C₁₋₆alkyl, optionally substituted aryl,        optionally substituted aryl C₁₋₆alkyl and optionally substituted        heteroalicyclic;        R¹⁵ is a group -M¹-M², wherein M¹ is selected from absent,        —C(═S)N(R¹³)—, —C(═NR¹⁴)N(R¹³)—, —SO₂N(R¹³)—, —SO₂—,        —C(═O)N(R¹³)—, —C(═O)C(═O)N(R¹³)—, —C₀₋₄alkylene-, —C(═O)—, and        an optionally substituted four to six-membered heterocyclyl        containing between one and three heteroatoms but comprising at        least one nitrogen; and M² is selected from —H, —C₀₋₆alkyl,        alkoxy, —C(═O)C₀₋₄alkylQ, —C₀₋₄alkylQ, —OC₀₋₄alkylQ-,        —N(R¹³)C₀₋₄alkylQ-, and —C(═O)N(R¹³)C₀₋₄alkylQ;        R⁶⁰ is selected from —H, halogen, trihalomethyl, —CN, —NO₂,        —NH₂, —OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³,        —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³ optionally        substituted C₁₋₆alkyl, optionally substituted aryl, optionally        substituted heteroaryl C₁₋₆alkyl, and optionally substituted        aryl C₁₋₆alkyl;        two of R⁶⁰, when attached to a non-aromatic carbon, can be oxo;        P¹ is a suitable leaving group; and        P² is selected from —H, a metal, and a group removed in-situ        when combining XXII and XXIII to make XXI.

In one example, the process is according to the preceding paragraph,wherein Ar is para-phenylene as defined by the substitution pattern of-Z- and —B-L-T about said phenylene.

In another example, the process is according to the preceding paragraph,wherein Z is either —O— or —NR⁵—.

In another example, the process is according to the preceding paragraph,wherein —B-L-T is selected from the following:

wherein Q, R²⁰, and R¹³ are as defined above; each E is selected from—O—, —N(R¹³)—, —CH₂, and —S(O)₀₋₂—; M is selected from —O—, —N(R¹³)—,—CH₂—, and —C(═O)N(R¹³)—; each V is independently either ═N— or ═C(H)—;each methylene in any of the above formulae is independently optionallysubstituted with R²⁵; and R²⁵ is selected from halogen, trihalomethyl,—CN, —NO₂, —NH₂, —OR³, —NR³R³, —S(O)O-2R³, —SO₂NR³R³, —CO₂R³,—C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionallysubstituted aryl, optionally substituted aryl C₁₋₆alkyl, heteroarylC₁₋₆alkyl, and optionally substituted C₁₋₆alkyl; two of R²⁵, togetherwith the carbon or carbons to which they are attached, can combine toform an optionally substituted three- to seven-membered alicyclic orheteroalicyclic; two of R²⁵ on a single carbon can be oxo.

In another example, the process is according to the preceding paragraph,wherein there is one of R¹ that is -D-R⁵⁰ and another of R¹ that is—OR^(3a).

In another example, the process is according to the preceding paragraph,wherein D is —O—.

In another example, the process is according to the preceding paragraph,wherein —O—R⁵⁰ and —OR^(3a) are interchangeably located at the6-position and 7-position of the quinazoline or quinoline according toFormula XXI.

In another example, the process is according to the preceding paragraph,wherein OR^(3a) is selected from —OH, —OSi(R⁵)(R⁵)R⁵, and optionallysubstituted —OC₁₋₆alkyl.

In another example, the process is according to the preceding paragraph,wherein J is ═N— or ═C(H)—.

In another example, the process is according to the preceding paragraph,wherein —B-L-T is selected from:

wherein Q, R²⁰, R¹³, E, and R⁶⁰ are as defined above; each methylene inany of the above formulae, other than those in a depicted ring, isindependently optionally substituted with R²⁵; and R²⁵ is selected fromhalogen, trihalomethyl, oxo, —CN, —NO₂, —NH₂, —OR³, —NR³R³, —S(O)₀₋₂R³,—SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³,—C(O)R³, optionally substituted aryl, optionally substituted arylC₁₋₆alkyl, heteroaryl C₁₋₆alkyl, and optionally substituted C₁₋₆alkyl;two of R²⁵, together with the carbon or carbons to which they areattached, can combine to form a three- to seven-membered optionallysubstituted alicyclic or heteroalicyclic.

In another example, the process is according to the preceding paragraph,wherein Q is selected from the following three formulae:

wherein R²⁰ is defined as above, and P is a five- to seven-memberedring, including the two shared carbons of the aromatic ring to which Pis fused, P optionally containing between one and three heteroatoms.

In another example, the process is according to the preceding paragraph,wherein —B-L-T is either of formula XXV or formula XXVI,

wherein R²⁰ is defined as above; G is either an optionally substitutedcycloalkyl or an optionally substituted heteroalicyclic; each R³⁰ isindependently selected from halogen, trihalomethyl, —CN, —NO₂, —NH₂,—OR³, —NR³R³, —S(O)₀₋₂R³, —SO₂NR³R³, —CO₂R³, —C(O)NR³R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally substitutedC₁₋₆alkyl; and R^(3a) and R^(3b) are each independently selected from —Hand optionally substituted C₁₋₆alkyl.

In another example, the process is according to the preceding paragraph,wherein a compound of formula XXIIa is combined with a compound offormula XXIIIa to make a compound of formula XXIa,

wherein —B-L-T, Z, J, R⁵⁰, and R² are as defined above; R⁷⁰ is selectedfrom —H, —NO₂, —NH₂, and —NR³R³; provided when Z is —N(R⁵)— that R⁵ isselected from —H, C₁₋₃alkyl, and aryl C₁₋₃alkyl; P¹ is selected fromhalogen, optionally substituted alkyl-S(O)₀₋₂—, optionally substitutedarylsulfonate, optionally substituted alkylsulfonate, a group containingboron, an azide, a group containing phosphorus, and a metal; and P² isselected from —H and a metal.

In another example, the process is according to the preceding paragraph,wherein P² is selected from —H, lithium, sodium, potassium, cesium,copper, palladium, and titanium.

In another example, the process is according to the preceding paragraph,wherein Z is —O—.

In another example, the process is according to the preceding paragraph,wherein P¹ is selected from chlorine, bromine, a toluene sulfonate, andtrifluoromethansulfonate.

In another example, the process is according to the preceding paragraph,wherein R⁷⁰ is —H.

In another example, the process is according to the preceding paragraph,wherein J is ═C(H)—.

In another example, the process is according to the preceding paragraph,wherein R² is selected from C₁₋₆ alkyl, perfluoro C₁₋₆ alkyl, andhalogen.

In another example, the process is according to the preceding paragraph,wherein XXIIa and XXIIIa are heated together, optionally with a base,optionally with microwave radiation, to form XXIa.

In another example, the process is according to the preceding paragraph,wherein the base is selected from an organic base, an inorganic base,and a combination of an organic base and an inorganic base.

In another example, the process is according to the preceding paragraph,wherein the base is selected from 2,6-lutidine,4-N,N-dimethylaminopyridine, and a metal carbonate.

In another example, the process is according to the preceding paragraph,wherein XXIIa and XXIIIa are heated together in a solvent with saidbase, at between about 40° C. and 200° C. for between about one hour andtwenty-four hours to form XXIa.

In another example, the process is according to the preceding paragraph,wherein the solvent is an organic solvent.

In another example, the process is according to the preceding paragraph,wherein one molar equivalent of XXIIa is combined with between about onequarter and four molar equivalents of XXIIIa.

In another example, the process is according to the preceding paragraph,wherein one molar equivalent of XXIIa is combined with more than one butless than two molar equivalents of XXIIIa.

In another example, the process is according to the preceding paragraph,wherein XXIIa is combined with XXIIIa and said base in an aromaticsolvent to form a mixture, and said mixture is heated to between about100° C. and 200° C. for between about one and ten hours to form Ia.

In another example, the process is according to the preceding paragraph,wherein the aromatic solvent is an optionally substituted benzene.

In another example, the process is according to the preceding paragraph,wherein the aromatic solvent is bromobenzene.

In another example, the process is according to the preceding paragraph,wherein the base is 4-N,N-dimethylaminopyridine.

In another example, the process is according to the preceding paragraph,wherein said mixture is heated to reflux for between about three andseven hours.

In another example, the process is according to the preceding paragraph,wherein said mixture is heated to reflux for between about four and sixhours.

In another example, the process is as defined seven paragraphs above,wherein one molar equivalent of XXIIa is combined with more than one butless than two molar equivalents of XXIIIa and said base in anon-aromatic solvent to form a mixture, and said mixture is heated tobetween about 40° C. and 100° C. for between about one and twenty hoursto form XXIa.

In another example, the process is according to the preceding paragraph,wherein the non-aromatic solvent comprises a functional group selectedfrom an amide, an ether, a nitrile, a halide, an ester, an amine, and aketone.

In another example, the process is according to the preceding paragraph,wherein the non-aromatic solvent is N,N-dimethylacetamide.

In another example, the process is according to the preceding paragraph,wherein the base is potassium carbonate.

In another example, the process is according to the preceding paragraph,wherein said mixture is heated to about 50° C. between about ten andtwenty hours.

In another example, the process is according to the preceding paragraph,wherein the aromatic solvent is an optionally substituted pyridine.

In another example, the process is according to the preceding paragraph,wherein the aromatic solvent is 2,6-lutidine.

In another example, the process is according to the preceding paragraph,wherein the base is 2,6-lutidine.

In another example, the process is according to the preceding paragraph,wherein said mixture is heated to reflux for between about three andseven hours.

In another example, the process is according to the preceding paragraph,wherein said mixture is heated to reflux for between about four and sixhours.

In another example, the process is as eighteen paragraphs defined above,wherein one molar equivalent of XXIIIa is combined with more than onebut less than two molar equivalents of XXIIa.

In another example, the process is according to the preceding paragraph,wherein XXIIa is combined with XXIIIa and said base in an aromaticsolvent to form a mixture, and said mixture is heated to between about100° C. and 200° C. for between about ten and twenty hours to form XXIa.

In another example, the process is according to the preceding paragraph,wherein the aromatic solvent is an optionally substituted pyridine.

In another example, the process is according to the preceding paragraph,wherein the aromatic solvent is 2,6-lutidine.

In another example, the process is according to the preceding paragraph,wherein the base is 2,6-lutidine.

In another example, the process is according to the preceding paragraph,wherein said mixture is heated to between about 150° C. and 200° C. forbetween about fifteen and twenty hours.

In another example, the process is as defined above in any of thetwenty-nine preceding paragraphs, wherein a compound of formula XXIIb issubstituted for the compound of formula XXIIa, and either a compound offormula XXIIIb or a compound of formula XXIIIc is substituted for thecompound of formula XXIIIa, in order to make a compound of formula XXIbor a compound of formula XXIc, respectively,

wherein J, R⁵⁰, R²⁰ and R² are as defined above.

In another example, the process is according to the preceding paragraph,wherein R², if present, is halogen.

In another example, the process is according to the preceding paragraph,wherein R², if present, is fluorine.

In another example, the process is according to the preceding paragraph,wherein R², if present, is up to two fluorines ortho to the oxygen ofthe phenylene to which R² is attached.

In another example, the process is used to make a compound listed ineither Table 1 or Table 2.

In another example the process is as defined above in any of thefifty-two preceding paragraphs, further comprising converting saidcompound to a pharmaceutically acceptable salt, hydrate, or prodrugthereof.

DEFINITIONS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise or they are expressly defined to mean something different.

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond. The symbol “

” refers to a group on a double-bond as occupying either position on theterminus of a double bond to which the symbol is attached; that is, thegeometry, E- or Z-, of the double bond is ambiguous. When a group isdepicted removed from its parent formula, the “˜” symbol will be used atthe end of the bond which was theoretically cleaved in order to separatethe group from its parent structural formula.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

In this application, some ring structures are depicted generically andwill be described textually. For example, in the schematic below, if inthe structure on the left, ring A is used to describe a “spirocyclyl,”then if ring A is cyclopropyl, there are at most four hydrogens on ringA (when “R” can also be —H). In another example, as depicted on theright side of the schematic below, if ring B is used to describe a“phenylene” then there can be at most four hydrogens on ring B (assumingdepicted cleaved bonds are not C—H bonds).

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted (forexample the —NH— in the formula above), implied (for example as in theformula above, where the hydrogens are not shown but understood to bepresent), or expressly defined hydrogen (for example where in theformula above, “X” equals ═CH—) from one of the ring atoms, so long as astable structure is formed. In the example depicted, the “R” group mayreside on either the 5-membered or the 6-membered ring of the fused ringsystem. In the formula depicted above, when y is 2 for example, then thetwo “R's” may reside on any two atoms of the ring system, again assumingeach replaces a depicted, implied, or expressly defined hydrogen on thering.

When there are more than one such depicted “floating” groups, as forexample in the formulae:

where there are two groups, namely, the “R” and the bond indicatingattachment to a parent structure; then, unless otherwise defined, the“floating” groups may reside on any atoms of the ring system, againassuming each replaces a depicted, implied, or expressly definedhydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Alkyl” is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof, inclusively. For example, “C₈alkyl” may refer to an n-octyl, iso-octyl, cyclohexylethyl, and thelike. Lower alkyl refers to alkyl groups of from one to six carbonatoms. Examples of lower alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and thelike. Higher alkyl refers to alkyl groups containing more that eightcarbon atoms. Exemplary alkyl groups are those of C₂₀ or below.Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groupsof from three to thirteen carbon atoms. Examples of cycloalkyl groupsinclude c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.In this application, alkyl refers to alkanyl, alkenyl, and alkynylresidues (and combinations thereof); it is intended to includecyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus when analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, either “butyl” or “C₄ alkyl” is meant toinclude n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-yneradicals; and for example, “propyl” or “C₃ alkyl” each include n-propyl,propenyl, and isopropyl.

“Alkylene” refers to straight or branched chain divalent radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation and having from one to ten carbon atoms, for example,methylene, ethylene, propylene, n-butylene and the like. Alkylene is asubset of alkyl, referring to the same residues as alkyl, but having twopoints of attachment and, specifically, fully saturated. Examples ofalkylene include ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—),dimethylpropylene (—CH₂C(CH₃)₂CH₂—), and cyclohexylpropylene(—CH₂CH₂CH(C₆H₁₃)).

“Alkylidene” refers to a straight or branched chain unsaturated divalentradical consisting solely of carbon and hydrogen atoms, having from twoto ten carbon atoms, for example, ethylidene, propylidene, n-butylidene,and the like. Alkylidene is a subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment and,specifically, double bond unsaturation. The unsaturation presentincludes at least one double bond.

“Alkylidyne” refers to a straight or branched chain unsaturated divalentradical consisting solely of carbon and hydrogen atoms having from twoto ten carbon atoms, for example, propylid-2-ynyl, n-butylid-1-ynyl, andthe like. Alkylidyne is a subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment and,specifically, triple bond unsaturation. The unsaturation presentincludes at least one triple bond.

Any of the above radicals, “alkylene,” “alkylidene” and “alkylidyne,”when optionally substituted, may contain alkyl substitution which itselfcontains unsaturation. For example,2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains ann-butylid-3-ynyl radical with a vinyl substituent at the 2-position ofsaid radical.

“Alkoxy” or “alkoxyl” refers to the group —O-alkyl, for exampleincluding from one to eight carbon atoms of a straight, branched, cyclicconfiguration, unsaturated chains, and combinations thereof attached tothe parent structure through an oxygen atom. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Substituted alkoxy” refers to the group —O-(substituted alkyl), thesubstitution on the alkyl group generally containing more than onlycarbon (as defined by alkoxy). One exemplary substituted alkoxy group is“polyalkoxy” or —O-optionally substituted alkylene-optionallysubstituted alkoxy, and includes groups such as —OCH₂CH₂OCH₃, and glycolethers such as polyethyleneglycol and —O(CH₂CH₂O)_(x)CH₃, where x is aninteger of between about two and about twenty, in another example,between about two and about ten, and in a further example between abouttwo and about five. Another exemplary substituted alkoxy group ishydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is for example an integer ofbetween about one and about ten, in another example y is an integer ofbetween about one and about four.

“Acyl” refers to groups of from one to ten carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to six carbons.

“α-Amino Acids” refer to naturally occurring and commercially availableamino acids and optical isomers thereof. Typical natural andcommercially available α-amino acids are glycine, alanine, serine,homoserine, threonine, valine, norvaline, leucine, isoleucine,norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine,arginine, cysteine, homocysteine, methionine, phenylalanine,homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine,para-tyrosine, tryptophan, glutamine, asparagine, proline andhydroxyproline. A “side chain of an α-amino acid” refers to the radicalfound on the α-carbon of an α-amino acid as defined above, for example,hydrogen (for glycine), methyl (for alanine), benzyl (forphenylalanine), and the like.

“Amino” refers to the group —NH₂. “Substituted amino,” refers to thegroup —N(H)R or —N(R)R where each R is independently selected from thegroup: optionally substituted alkyl, optionally substituted alkoxy,optionally substituted aryl, optionally substituted heterocyclyl, acyl,carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example,diethylamino, methylsulfonylamino, furanyl-oxy-sulfonamino.

“Aryl” refers to aromatic six- to fourteen-membered carbocyclic ring,for example, benzene, naphthalene, indane, tetralin, fluorene and thelike, univalent radicals. As univalent radicals, the aforementioned ringexamples are named, phenyl, naphthyl, indanyl, tetralinyl, andfluorenyl.

“Arylene” generically refers to any aryl that has at least two groupsattached thereto. For a more specific example, “phenylene” refers to adivalent phenyl ring radical. A phenylene, thus may have more than twogroups attached, but is defined by a minimum of two non-hydrogen groupsattached thereto.

“Arylalkyl” refers to a residue in which an aryl moiety is attached to aparent structure via one of an alkylene, alkylidene, or alkylidyneradical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyland the like. Both the aryl, and the corresponding alkylene, alkylidene,or alkylidyne radical portion of an arylalkyl group may be optionallysubstituted. “Lower arylalkyl” refers to an arylalkyl where the “alkyl”portion of the group has one to six carbons; this can also be referredto as C₁₋₆ arylalkyl.

“Exo-alkenyl” refers to a double bond that emanates from an annularcarbon, and is not within the ring system, for example the double bonddepicted in the formula below.

In some examples, as appreciated by one of ordinary skill in the art,two adjacent groups on an aromatic system may be fused together to forma ring structure. The fused ring structure may contain heteroatoms andmay be optionally substituted with one or more groups. It shouldadditionally be noted that saturated carbons of such fused groups (i.e.saturated ring structures) can contain two substitution groups.

“Fused-polycyclic” or “fused ring system” refers to a polycyclic ringsystem that contains bridged or fused rings; that is, where two ringshave more than one shared atom in their ring structures. In thisapplication, fused-polycyclics and fused ring systems are notnecessarily all aromatic ring systems. Typically, but not necessarily,fused-polycyclics share a vicinal set of atoms, for example naphthaleneor 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have spiro rings attached thereto via asingle ring atom of the fused-polycyclic.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.“Haloalkyl” and “haloaryl” refer generically to alkyl and aryl radicalsthat are substituted with one or more halogens, respectively. Thus,“dihaloaryl,” “dihaloalkyl,” “trihaloaryl” etc. refer to aryl and alkylsubstituted with a plurality of halogens, but not necessarily aplurality of the same halogen; thus 4-chloro-3-fluorophenyl is withinthe scope of dihaloaryl.

“Heteroarylene” generically refers to any heteroaryl that has at leasttwo groups attached thereto. For a more specific example, “pyridylene”refers to a divalent pyridyl ring radical. A pyridylene, thus may havemore than two groups attached, but is defined by a minimum of twonon-hydrogen groups attached thereto.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” refers to a stable three- to fifteen-membered ringradical that consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclyl radical may bea monocyclic, bicyclic or tricyclic ring system, which may include fusedor bridged ring systems as well as spirocyclic systems; and thenitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radicalmay be optionally oxidized to various oxidation states. In a specificexample, the group —S(O)₀₋₂—, refers to —S— (sulfide), —S(O)—(sulfoxide), and —SO₂— (sulfone). For convenience, nitrogens,particularly but not exclusively, those defined as annular aromaticnitrogens, are meant to include their corresponding N-oxide form,although not explicitly defined as such in a particular example. Thus,for a compound of the invention having, for example, a pyridyl ring; thecorresponding pyridyl-N-oxide is meant to be included as anothercompound of the invention. In addition, annular nitrogen atoms may beoptionally quaternized; and the ring radical may be partially or fullysaturated or aromatic. Examples of heterocyclyl radicals include, butare not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

“Heteroalicyclic” refers specifically to a non-aromatic heterocyclylradical. A heteroalicyclic may contain unsaturation, but is notaromatic.

“Heteroaryl” refers specifically to an aromatic heterocyclyl radical.

“Heterocyclylalkyl” refers to a residue in which a heterocyclyl isattached to a parent structure via one of an alkylene, alkylidene, oralkylidyne radical. Examples include (4-methylpiperazin-1-yl)methyl,(morpholin-4-yl)methyl, (pyridine-4-yl)methyl, 2-(oxazolin-2-yl)ethyl,4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. Both theheterocyclyl, and the corresponding alkylene, alkylidene, or alkylidyneradical portion of a heterocyclylalkyl group may be optionallysubstituted. “Lower heterocyclylalkyl” refers to a heterocyclylalkylwhere the “alkyl” portion of the group has one to six carbons.“Heteroalicyclylalkyl” refers specifically to a heterocyclylalkyl wherethe heterocyclyl portion of the group is non-aromatic; and“heteroarylalkyl” refers specifically to a heterocyclylalkyl where theheterocyclyl portion of the group is aromatic Such terms may bedescribed in more than one way, for example, “lower heterocyclylalkyl”and “heterocyclyl C₁₋₆alkyl” are equivalent terms.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that,with respect to any molecule described as containing one or moreoptional substituents, that only sterically practical and/orsynthetically feasible compounds are meant to be included. “Optionallysubstituted” refers to all subsequent modifiers in a term, for examplein the term “optionally substituted arylC₁₋₈ alkyl,” optionalsubstitution may occur on both the “C₁₋₈alkyl” portion and the “aryl”portion of the molecule; and for example, optionally substituted alkylincludes optionally substituted cycloalkyl groups, which in turn aredefined as including optionally substituted alkyl groups, potentially adinfinitum. A list of exemplary optional substitution are listed below inthe definition of “substituted.”

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.”

“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from aparticular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto. Aspirocyclyl can be carbocyclic or heteroalicyclic.

“Substituted” alkyl, aryl, and heterocyclyl, refer respectively toalkyl, aryl, and heterocyclyl, wherein one or more (for example up toabout five, in another example, up to about three) hydrogen atoms arereplaced by a substituent independently selected from: optionallysubstituted alkyl (for example, fluoromethyl), optionally substitutedaryl (for example, 4-hydroxyphenyl), optionally substituted arylalkyl(for example, 1-phenyl-ethyl), optionally substituted heterocyclylalkyl(for example, 1-pyridin-3-yl-ethyl), optionally substituted heterocyclyl(for example, 5-chloro-pyridin-3-yl or 1-methyl-piperidin-4-yl),optionally substituted alkoxy, alkylenedioxy (for examplemethylenedioxy), optionally substituted amino (for example, alkylaminoand dialkylamino), optionally substituted amidino, optionallysubstituted aryloxy (for example, phenoxy), optionally substitutedarylalkyloxy (for example, benzyloxy), carboxy (—CO₂H), carboalkoxy(that is, acyloxy or —OC(═O)R), carboxyalkyl (that is, esters or —CO₂R),carboxamido, benzyloxycarbonylamino (CBZ-amino), cyano, acyl, halogen,hydroxy, nitro, sulfanyl, sulfinyl, sulfonyl, thiol, halogen, hydroxy,oxo, carbamyl, acylamino, and sulfonamido.

“Suitable leaving group” is defined as the term would be understood byone of ordinary skill in the art; that is, a carbon with such a groupattached, upon reaction wherein a new bond is to be formed, loses such agroup upon formation of the new bond. The invention pertainsparticularly with respect convergent synthesis, to reactions where sucha leaving group is bonded to a reaction partner that is aromatic,undergoes a bond-forming reaction and remains aromatic. A typicalexample of such a reaction is a nucleophilic aromatic substitutionreaction, as would be understood by one of ordinary skill in the art.However, the invention is not limited to such mechanistic restrictions;for example, reactions where there is, for example, an insertionreaction (for example by a transition metal) into the bond between thearomatic reaction partner and its leaving group followed by reductivecoupling can also be used within the scope of the invention. Examples ofsuitable leaving groups include halogens, optionally substituted aryl oralkyl sulfonates, phosphonates, azides, RS(O)₀₋₂— where R is, forexample optionally substituted alkyl, optionally substituted aryl, oroptionally substituted heteroaryl.

“Sulfanyl” refers to the groups: —S-(optionally substituted alkyl),—S-(optionally substituted aryl), and —S-(optionally substitutedheterocyclyl).

“Sulfinyl” refers to the groups: —S(O)—H, —S(O)-(optionally substitutedalkyl), —S(O)-optionally substituted aryl), and —S(O)-(optionallysubstituted heterocyclyl).

“Sulfonyl” refers to the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-(optionally substituted heterocyclyl), —S(O₂)-(optionallysubstituted alkoxy), —S(O₂)-optionally substituted aryloxy), and—S(O₂)-(optionally substituted heterocyclyloxy).

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

Some of the compounds of the invention may have imino, amino, oxo orhydroxy substituents off aromatic heterocyclyl systems. For purposes ofthis disclosure, it is understood that such imino, amino, oxo or hydroxysubstituents may exist in their corresponding tautomeric form, i.e.,amino, imino, hydroxy or oxo, respectively.

Compounds of the invention are named according to systematic applicationof the nomenclature rules agreed upon by the International Union of Pureand Applied Chemistry (IUPAC), International Union of Biochemistry andMolecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure.

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

It is assumed that when considering generic descriptions of compounds ofthe invention for the purpose of constructing a compound, suchconstruction results in the creation of a stable structure. That is, oneof ordinary skill in the art would recognize that there cantheoretically be some constructs which would not normally be consideredas stable compounds (that is, sterically practical and/or syntheticallyfeasible, supra).

When a particular group with its bonding structure is denoted as beingbonded to two partners; that is, a divalent radical, for example,—OCH₂—, then it is understood that either of the two partners may bebound to the particular group at one end, and the other partner isnecessarily bound to the other end of the particular group, unlessstated explicitly otherwise. Stated another way, divalent radicals arenot to be construed as limited to the depicted orientation, for example“—OCH₂-” is meant to mean not only “—OCH₂—” as drawn, but also “—CH₂O—.”

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a preferred embodiment the patient is a mammal, and ina most preferred embodiment the patient is human.

“Kinase-dependent diseases or conditions” refer to pathologic conditionsthat depend on the activity of one or more protein kinases. Kinaseseither directly or indirectly participate in the signal transductionpathways of a variety of cellular activities including proliferation,adhesion, migration, differentiation and invasion. Diseases associatedwith kinase activities include tumor growth, the pathologicneovascularization that supports solid tumor growth, and associated withother diseases where excessive local vascularization is involved such asocular diseases (diabetic retinopathy, age-related macular degeneration,and the like) and inflammation (psoriasis, rheumatoid arthritis, and thelike).

While not wishing to be bound to theory, phosphatases can also play arole in “kinase-dependent diseases or conditions” as cognates ofkinases; that is, kinases phosphorylate and phosphatasesdephosphorylate, for example protein substrates. Therefore compounds ofthe invention, while modulating kinase activity as described herein, mayalso modulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. In any case, as statedpreviously, the compounds of the invention are useful for treatingdiseases characterized in part by abnormal levels of cell proliferation(i.e. tumor growth), programmed cell death (apoptosis), cell migrationand invasion and angiogenesis associated with tumor growth.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinorna, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinorna, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis defomians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal lands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

“Pharmaceutically acceptable acid addition salt” refers to those saltsthat retain the biological effectiveness of the free bases and that arenot biologically or otherwise undesirable, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, as well as organic acids such as aceticacid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Exemplary salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplaryorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline, and caffeine. (See, forexample, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977; 66:1-19 which is incorporated herein by reference.)

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)wherein the alkyl group is a straight or branched chain. Acceptableesters also include cycloalkyl esters and arylalkyl esters such as, butnot limited to benzyl. Examples of pharmaceutically acceptable amides ofthe compounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

“Treating” or “treatment” as used herein covers the treatment of adisease-state in a human, which disease-state is characterized byabnormal cellular proliferation, and invasion and includes at least oneof: (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it; (ii) inhibiting the disease-state,i.e., arresting its development; and (iii) relieving the disease-state,i.e., causing regression of the disease-state. As is known in the art,adjustments for systemic versus localized delivery, age, body weight,general health, sex, diet, time of administration, drug interaction andthe severity of the condition may be necessary, and will beascertainable with routine experimentation by one of ordinary skill inthe art.

One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes, in particular c-Met, c-Kit, KDR,flt-3, or flt-4-ligand complexes, and their corresponding x-raystructure coordinates can be used to reveal new structural informationuseful for understanding the biological activity of kinases as describedherein. As well, the key structural features of the aforementionedproteins, particularly, the shape of the ligand binding site, are usefulin methods for designing or identifying selective modulators of kinasesand in solving the structures of other proteins with similar features.Such protein-ligand complexes, having compounds of the invention astheir ligand component, are an aspect of the invention.

As well, one of ordinary skill in the art would appreciate that suchsuitable x-ray quality crystals can be used as part of a method ofidentifying a candidate agent capable of binding to and modulating theactivity of kinases. Such methods may be characterized by the followingaspects: a) introducing into a suitable computer program, informationdefining a ligand binding domain of a kinase in a conformation (e.g. asdefined by x-ray structure coordinates obtained from suitable x-rayquality crystals as described above) wherein the computer programcreates a model of the three dimensional structures of the ligandbinding domain, b) introducing a model of the three dimensionalstructure of a candidate agent in the computer program, c) superimposingthe model of the candidate agent on the model of the ligand bindingdomain, and d) assessing whether the candidate agent model fitsspatially into the ligand binding domain. Aspects a-d are notnecessarily carried out in the aforementioned order. Such methods mayfurther entail: performing rational drug design with the model of thethree-dimensional structure, and selecting a potential candidate agentin conjunction with computer modeling.

Additionally, one skilled in the art would appreciate that such methodsmay further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor kinase modulation, and determining whether said candidate agentmodulates kinase activity in the assay. Such methods may also includeadministering the candidate agent, determined to modulate kinaseactivity, to a mammal suffering from a condition treatable by kinasemodulation, such as those described above.

Also, one skilled in the art would appreciate that compounds of theinvention can be used in a method of evaluating the ability of a testagent to associate with a molecule or molecular complex comprising aligand binding domain of a kinase. Such a method may be characterized bythe following aspects: a) creating a computer model of a kinase bindingpocket using structure coordinates obtained from suitable x-ray qualitycrystals of the kinase, b) employing computational algorithms to performa fitting operation between the test agent and the computer model of thebinding pocket, and c) analyzing the results of the fitting operation toquantify the association between the test agent and the computer modelof the binding pocket.

General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc. Compositions of the invention may be used incombination with anticancer or other agents that are generallyadministered to a patient being treated for cancer. Adjuvants includepreserving, wetting, suspending, sweetening, flavoring, perfuming,emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylalted hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One preferable route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 1,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is an example. The specific dosage used,however, can vary. For example, the dosage can depend on a number offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

Utility of Compounds of the Invention as Screening Agents

To employ the compounds of the invention in a method of screening forcandidate agents that bind to, for example c-Met, KDR, c-Kit, flt-3, orflt-4, the protein is bound to a support, and a compound of theinvention is added to the assay. Alternatively, the compound of theinvention is bound to the support and the protein is added. Classes ofcandidate agents among which novel binding agents may be sought includespecific antibodies, non-natural binding agents identified in screens ofchemical libraries, peptide analogs, etc. Of particular interest arescreening assays for candidate agents that have a low toxicity for humancells. A wide variety of assays may be used for this purpose, includinglabeled in vitro protein-protein binding assays, electrophoreticmobility shift assays, immunoassays for protein binding, functionalassays (phosphorylation assays, etc.) and the like.

The determination of the binding of the candidate agent to, for example,c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be done in a number ofways. In one example, the candidate agent (the compound of theinvention) is labeled, for example, with a fluorescent or radioactivemoiety and binding determined directly. For example, thus may be done byattaching all or a portion of the c-Met, KDR, c-Kit, flt-3, or flt-4protein to a solid support, adding a labeled agent (for example acompound of the invention in which at least one atom has been replacedby a detectable isotope), washing off excess reagent, and determiningwhether the amount of the label is that present on the solid support.Various blocking and washing steps may be utilized as is known in theart.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal,e.g., radioisotope, fluorescent tag, enzyme, antibodies, particles suchas magnetic particles, chemiluminescent tag, or specific bindingmolecules, etc. Specific binding molecules include pairs, such as biotinand streptavidin, digoxin and antidigoxin etc. For the specific bindingmembers, the complementary member would normally be labeled with amolecule which provides for detection, in accordance with knownprocedures, as outlined above. The label can directly or indirectlyprovide a detectable signal.

In some embodiments, only one of the components is labeled. For example,c-Met, KDR, c-Kit, flt-3, or flt-4 protein may be labeled at tyrosinepositions using ¹²⁵I, or with fluorophores. Alternatively, more than onecomponent may be labeled with different labels; using ¹²⁵I for theproteins, for example, and a fluorophore for the candidate agents.

The compounds of the invention may also be used as competitors to screenfor additional drug candidates. “Candidate bioactive agent” or “drugcandidate” or grammatical equivalents as used herein describe anymolecule, e.g., protein, oligopeptide, small organic molecule,polysaccharide, polynucleotide, etc., to be tested for bioactivity. Theymay be capable of directly or indirectly altering the cellularproliferation phenotype or the expression of a cellular proliferationsequence, including both nucleic acid sequences and protein sequences.In other cases, alteration of cellular proliferation protein bindingand/or activity is screened. In the case where protein binding oractivity is screened, some embodiments exclude molecules already knownto bind to that particular protein. Exemplary embodiments of assaysdescribed herein include candidate agents, which do not bind the targetprotein in its endogenous native state, termed herein as “exogenous”agents. In one example, exogenous agents further exclude antibodies toc-Met, KDR, c-Kit, flt-3, or flt-4.

Candidate agents can encompass numerous chemical classes, thoughtypically they are organic molecules having a molecular weight of morethan about 100 daltons and less than about 2,500 daltons. Candidateagents comprise functional groups necessary for structural interactionwith proteins, particularly hydrogen bonding and lipophilic binding, andtypically include at least an amine, carbonyl, hydroxyl, ether, orcarboxyl group, for example at least two of the functional chemicalgroups. The candidate agents often comprise cyclical carbon orheterocyclyl structures and/or aromatic or polyaromatic structuressubstituted with one or more of the above functional groups. Candidateagents are also found among biomolecules including peptides,saccharides, fatty acids, steroids, purines, pyrimidines, derivatives,structural analogs, or combinations thereof.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides. Alternatively, libraries of natural compounds in theform of bacterial, fungal, plant and animal extracts are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification to producestructural analogs.

In one example, the binding of the candidate agent is determined throughthe use of competitive binding assays. In this example, the competitoris a binding moiety known to bind to c-Met, KDR, c-Kit, flt-3, or flt-4,such as an antibody, peptide, binding partner, ligand, etc. Undercertain circumstances, there may be competitive binding as between thecandidate agent and the binding moiety, with the binding moietydisplacing the candidate agent.

In some embodiments, the candidate agent is labeled. Either thecandidate agent, or the competitor, or both, is added first to forexample c-Met, KDR, c-Kit, flt-3, or flt-4 for a time sufficient toallow binding, if present. Incubations may be performed at anytemperature that facilitates optimal activity, typically between 4° C.and 40° C. Incubation periods are selected for optimum activity, but mayalso be optimized to facilitate rapid high throughput screening.Typically between 0.1 and 1 hour will be sufficient. Excess reagent isgenerally removed or washed away. The second component is then added,and the presence or absence of the labeled component is followed, toindicate binding.

In one example, the competitor is added first, followed by the candidateagent. Displacement of the competitor is an indication the candidateagent is binding to c-Met, KDR, c-Kit, flt-3, or flt-4 and thus iscapable of binding to, and potentially modulating, the activity of thec-Met, KDR, c-Kit, flt-3, or flt-4. In this embodiment, either componentcan be labeled. Thus, for example, if the competitor is labeled, thepresence of label in the wash solution indicates displacement by theagent. Alternatively, if the candidate agent is labeled, the presence ofthe label on the support indicates displacement.

In an alternative embodiment, the candidate agent is added first, withincubation and washing, followed by the competitor. The absence ofbinding by the competitor may indicate the candidate agent is bound toc-Met, KDR, c-Kit, flt-3, or flt-4 with a higher affinity. Thus, if thecandidate agent is labeled, the presence of the label on the support,coupled with a lack of competitor binding, may indicate the candidateagent is capable of binding to c-Met, KDR, c-Kit, flt-3, or flt-4.

It may be of value to identify the binding site of c-Met, KDR, c-Kit,flt-3, or flt-4. This can be done in a variety of ways. In oneembodiment, once c-Met, KDR, c-Kit, flt-3, or flt-4 has been identifiedas binding to the candidate agent, the c-Met, KDR, c-Kit, flt-3, orflt-4 is fragmented or modified and the assays repeated to identify thenecessary components for binding.

Modulation is tested by screening for candidate agents capable ofmodulating the activity of c-Met, KDR, c-Kit, flt-3, or flt-4 comprisingthe steps of combining a candidate agent with c-Met, KDR, c-Kit, flt-3,or flt-4, as above, and determining an alteration in the biologicalactivity of the c-Met, KDR, c-Kit, flt-3, or flt-4. Thus, in thisembodiment, the candidate agent should both bind to (although this maynot be necessary), and alter its biological or biochemical activity asdefined herein. The methods include both in vitro screening methods andin vivo screening of cells for alterations in cell viability,morphology, and the like.

Alternatively, differential screening may be used to identify drugcandidates that bind to native c-Met, KDR, c-Kit, flt-3, or flt-4, butcannot bind to modified c-Met, KDR, c-Kit, flt-3, or flt-4.

Positive controls and negative controls may be used in the assays. Forexample, all control and test samples are performed in at leasttriplicate to obtain statistically significant results. Incubation ofsamples is for a time sufficient for the binding of the agent to theprotein. Following incubation, samples are washed free ofnon-specifically bound material and the amount of bound, generallylabeled agent determined. For example, where a radiolabel is employed,the samples may be counted in a scintillation counter to determine theamount of bound compound.

A variety of other reagents may be included in the screening assays.These include reagents like salts, neutral proteins, e.g., albumin,detergents, etc which may be used to facilitate optimal protein-proteinbinding and/or reduce non-specific or background interactions. Alsoreagents that otherwise improve the efficiency of the assay, such asprotease inhibitors, nuclease inhibitors, anti-microbial agents, etc.,may be used. The mixture of components may be added in any order thatprovides for the requisite binding.

ABBREVIATIONS AND THEIR DEFINITIONS

The following abbreviations and terms have the indicated meaningsthroughout.

Abbreviation Meaning Ac acetyl ATP adenosine triphosphate BNB4-bromomethyl-3-nitrobenzoic acid Boc t-butyloxy carbonyl br broad Bubutyl ° C. degrees Celsius c- cyclo CBZ CarboBenZoxy = benzyloxycarbonyld doublet dd doublet of doublet dt doublet of triplet DBUDiazabicyclo[5.4.0]undec-7-ere DCM dichloromethane = methylene chloride= CH₂Cl₂ DCE dichloroethylene DEAD diethyl azodicarboxylate DICdiisopropylcarbodiimide DIEA N,N-diisopropylethyl amine DMAP4-N,N-dimethylaminopyridine DMF N,N-dimethylfonnamide DMSO dimethylsulfoxide DVB 1,4-divinylbenzene EEDQ2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline EI Electron Impactionization Et ethyl Fmoc 9-fluorenylmethoxycarbonyl g gram(s) GC gaschromatography h or hr hour(s) HATU0-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HMDS hexamethyldisilazane HOAc acetic acid HOBthydroxybenzotriazole HPLC high pressure liquid chromatography L liter(s)M molar or molarity m multiplet Me methyl mesyl methanesulfonyl mgmilligram(s) MHz megahertz (frequency) Min minute(s) mL milliliter(s) mMmillimolar mmol millimole(s) mol mole(s) MS mass spectral analysis MTBEmethyl t-butyl ether N normal or normality NBS N-bromosuccinimide NCSN-chlorosuccinimide nM nanomolar NMO N-methylmorpholine oxide NMRnuclear magnetic resonance spectroscopy PEG polyethylene glycol pEYpoly-glutamine, tyrosine Ph phenyl PhOH phenol PfP pentafluorophenolPfPy pentafluoropyridine PPTS Pyridinium p-toluenesulfonate Py pyridinePyBroP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate q quartetRT Room temperature Sat'd saturated s singlet s- secondary t- tertiary tor tr triplet TBDMS t-butyldimethylsilyl TES triethylsilane TFAtrifluoroacetic acid THF tetrahydrofuran TMOF trimethyl orthoformate TMStrimethylsilyl tosyl p-toluenesulfonyl Trt triphenylmethyl uLmicroliter(s) uM Micromole(s) or micromolar

Synthesis of Compounds

Schemes 1 and 2 depict general synthetic routes for compounds of theinvention and are not intended to be limiting. More specifically, Scheme1 depicts synthesis of quinazoline compounds, and Scheme 2 depictssynthesis of quinoline compounds. Specific examples are describedsubsequently to these general synthetic descriptions so as to allow oneskilled in the art to make and use either quinazolines or quinolines ofthe invention.

Referring to Scheme 1, a benzoic ester 1, where R is typically but notnecessarily a methyl radical and P is typically but not necessarily analkyl group, is O-alkylated at the oxygen para to the carboxylate groupwith an electrophile to afford a substituted derivative 2. P istypically a lower alkyl group, but may be a protecting group that isremoved later in a synthesis. When P is a lower alkyl group it maypossess functionality initially, or be derivatized to contain suchfunctionality at various stages of the synthesis. The group, E¹, mayrepresent either a protecting group, e.g. benzyl, or a group that eitherhas moieties present in compounds of the invention or possessesfunctionality that serve as a precursors to such groups. Aromatic ringnitration and reduction of the corresponding nitro group are carried outin a regio- and chemoselective manner by methods well known in the artto give anthranilate derivative 3. Formation of quinazolin-4-one 4 iscarried out by methods well known in the art, for example by heating 3in formamide solution in the presence of ammonium formate or for exampleby heating directly with formamidine hydrochloride. Introduction of4-position functionality groups is carried out by methods known in theart. For example, quinazolin-4-one 4 is converted to an intermediatequinazoline 5, where “L” represents a leaving group, e.g. chlorine.Quinazoline 5 is then converted to 6 by reaction with a range ofnucleophiles, e.g. amines, alcohols, and thiols. After formation of 6,group “Z” is either left “as is” or converted at some subsequent stageto a derivative thereof. For example when Z is —NH—, then the hydrogenon the nitrogen may optionally be replaced with an alkyl group, or whenZ is sulfur, then that sulfur atom may be oxidized to, for example, asulfone. Structure 6 may represent compounds of the invention or, forexample when E¹ serves as a protecting group, E¹ may be removed toprovide phenol 7. Introduction of a group E² is carried out by methodswell established in the art; for example alkylation with anappropriately derivatized alkyl halide (or mesylate or the like) to give8 which also represents compounds of the invention.

Scheme 2 shows a general route used to make exemplary quinolines of theinvention. For example, compound 9 contains an alkyl group, R¹, aprotecting group, P. The arrangement of the protected and alkylatedphenolic oxygens may vary from the pattern depicted in compound 9.Compound 9 is nitrated to provide compound 10. The nitro group ofcompound 10 is reduced to give aniline 11. Compound 11 is treated, forexample, with ethyl formate under basic conditions followed byacidification and isolation to form 4-hydroxy quinoline 12. Quinoline 12may be converted to compounds of the invention in a number of ways. Forexample, the 4-oxygen is used as a nucleophile in a nucleophilicaromatic substitution reaction to form quinoline-aryl-ether 13. Inanother example, compound 13 is further derivatized, via removal ofprotecting group P, to afford compound 14. The 7-hydroxy of compound 14is alkylated, for example with electrophile E, to provide a compound ofthe invention. As discussed in relation to Scheme 1, variations on anyof the above steps are possible, and intermediates in these schemes, forexample compounds 12, 13, and 14 may also be compounds of the inventionaccording to formula I. Also, for example, the 4-hydroxy quinolinecompound 12 are converted to a corresponding 4-nitrogen or 4-sulfurquinoline using chemistry known in the art to make compounds of theinvention, or alternatively the corresponding 4-nitrogen or 4-sulfurquinolines are made via routes analogous to that depicted in Schemes 1and 2.

Schemes 1 and 2 are illustrative of quinolines and quinazolines havingoxygen substitution at their respective 6- and 7-positions; theinvention is not so limited, but rather is intended to encompassquinolines and quinazolines not necessarily having substitution, oxygenor otherwise, at their respective 6- or 7-positions.

Schemes 3 and 4 depict generalized synthetic routes to show the processof the invention to make compounds of formula XXI and is not intended tobe limiting. More specifically, Schemes 3 and 4 depict convergentsyntheses of quinoline and quinazoline compounds as described herein.Specific examples are described subsequently to this general syntheticdescription so as to allow one of ordinary skill in the art to practicethe invention.

Referring to Scheme 3, a benzoic ester 16 for example, where R istypically but not necessarily a methyl radical and R¹ is typically butnot necessarily one or more alkoxy or hydroxy groups. In a typicalsynthesis, at least one of R¹ within Scheme 3 is a hydroxyl which isconverted (or protected) via one or more steps to a group important tothe activity of the compounds as described as kinase modulators (in thecase that —OH itself is desired in the final compound, then deprotectionaffords the —OH, vide supra). Preferably, but not necessarily, thisgroup is complete once the synthesis of XXII is complete. By buildingdesired complexity into XXII prior to combination with XXIII, convergentsyntheses' advantages over serial syntheses are realized more fully.Regioselective aromatic ring nitration, and reduction of thecorresponding nitro group, are carried out in a regio- andchemoselective manner by methods well known in the art to giveanthranilate derivative 17. Formation of quinazoline or quinoline 4-one18 is carried out by methods well known in the art. For example byheating 17 in formamide solution in the presence of ammonium formate, orby heating 17 with formamidine hydrochloride, the quinazoline-4-oneanalog is made. In another example 17 is treated, for example, withethyl formate under basic conditions followed by acidification andisolation to form the 4-hydroxy quinoline analog (a tautomer of the4-one). In this scheme J′ represents either carbon or nitrogen atom withthe appropriate number of hydrogens to fill their respective normalvalence bonding schemes; J′ is a precursor to J. Radicals J and R⁷⁰ arein accord with formula XXI. Introduction of 4-position functionality iscarried out by methods known in the art. For example, 4-one 18 isconverted to XXII, where “P¹” represents a suitable leaving group (inaccord with formula XXI), e.g. chlorine (via dehydration/chlorination of18 to give XXII). In another example, a 4-hydroxy analog is converted toa sulfonyl ester, e.g. the trifluoromethane sulfonate.

Scheme 4 shows a general route used to make compounds of formula XXIII.For example, aromatic compound 19, where “X” is a leaving group, such asfluorine and “E” is an electron withdrawing group such as nitro, isconverted to 20 by reaction with a range of nucleophiles, e.g. amines,alcohols, and thiols (where “Z” is oxygen, nitrogen (substituted ornot), or sulfur). In this case, “R” represents a removable group, forexample benzyl. In a typical synthesis, after formation of 20, group “E”is either left “as is” or converted at some subsequent stage to aderivative thereof. In the example depicted, E is converted to B′, aprecursor to B in accord with formula XXI, to make 21. For example if Eis a nitro, then B′ could might be an amino group, made via reduction ofthe nitro group. Structure 21 may be further derivatized by synthesis of—B-L-T in accord with formula XXI. In scheme 4, this is depicted as aserial process whereby L′, a precursor to L, is introduced to give 22,followed by introduction of T′ (a precursor to T) to give 23. In somecases, -L-T is preformed and appended to B. One of ordinary skill in theart would appreciate that variations on any of the above steps arepossible. Compound 23 is converted to XXIII via conversion of T′ to Tand introduction of P² (for example, when R is benzyl, removal of thebenzyl after completion of —B-L-T).

As discussed above, one aspect of the invention encompasses combinationof XXII and XXIII to make compounds of formula XXI. Because of thediversity and complexity of compounds described for kinase modulation(vide supra), methods of the invention provide advantages to serialsynthesis.

EXAMPLES

The following examples serve to more fully describe the manner of usingthe above-described invention, as well as to set forth the best modescontemplated for carrying out various aspects of the invention. It isunderstood that these examples in no way serve to limit the true scopeof this invention, but rather are presented for illustrative purposes.All references cited herein are incorporated by reference in theirentirety. Generally, but not necessarily, each example set out belowdescribes a multi-step synthesis as outlined above.

Quinoline and Quinazoline Syntheses Example 1

Synthesis of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone.1-(4-Benzyloxy-3-methoxy-phenyl)-ethanone (200 mmol, 51.3 g) dissolvedin DCM (750 ml) and the mixture cooled to 0° C. Nitric acid (90%, 300mmol, 14 ml) was added dropwise to the cooled solution over 20 minutes.Sulfuric acid (96.2%, 300 mmol, 8.75 ml) was then added dropwise over 40minutes at 0° C.

Additional nitric acid (200 mmol, 9.4 ml) was added dropwise over 20minutes. The reaction mixture was diluted with water (300 ml) and washwith water (3×200 ml), Sat. NaHCO₃ (4×200 ml, or until neutral). Theorganic layer was dried over Na₂SO₄ and concentrated.

The crude mixture was recrystallized with DMF to give 22.5 g of thenitro product. The DMF layer was concentrated and recrystallized withethyl acetate to give additional 8.75 g of the product. The ethylacetate layer was concentrated and purified on silica column using 20%EtOAc/hexanes to gave another 4.75 g of the product. Total yield is 36g, (˜60%). ¹H NMR (CDCl₃): 7.647 (1H, s), 7.446-7.333 (5H, m), 6.745(1H, s), 5.210 (2H, s), 3.968 (3H, s), 2.487 (3H, s).

Example 2

Synthesis of 1-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone. AMixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31.g), 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (120 mmol, 36 g),toluene (500 ml) and water (500 ml) was refluxed overnight, or untilcompletion. The mixture was filtered through celite and washed withEtOAc. The organic layer was washed with water and Sat. NaCl, dried overNa₂SO₄, and concentrated to afford the product, 90%. ¹H NMR (CDCl₃):7.408-7.298 (5H, m), 7.130 (1H, s), 6.155 (2H, br), 6.104 (1H, s), 5.134(2H, s), 3.834 (3H, s), 2.507 (3H, s). LC/MS (M+1=272).

Example 3

Synthesis of 7-Benzyloxy-6-methoxy-quinolin-4-ol. To a solution of1-(2-Amino-4-benzyloxy-5-methoxy-phenyl)-ethanone (108 mmol, 29.3 g) inDME (700 ml) was added sodium methoxide (432 mmol, 23.35 g). The mixturewas stirred for 30 minutes. Ethyl formate (540 mmol, 44 ml) was addedand the mixture was stirred overnight. (Additional sodium methoxide maybe needed if reaction is not complete as monitored by LC/MS.) After thereaction was completion, the mixture was diluted with water (40 ml) andacidified to neutral with 1M HCl. The precipitate was filtered andwashed with water, dried in vacuo to afford 22 g (72%) of7-benzyloxy-6-methoxy-quinolin-4-ol. ¹H NMR (CDCl₃): 10.7 (1H, br),7.703 (1H, s), 7.493-7.461 (1H, t), 7.431-7.413 (2H, br d), 7.372-7.333(2H, t), 7.296-7.283 (1H, d), 6.839 (1H, s), 6.212-6.193 (1H, d), 5.212(2H, s), 3.965 (3H, s). LC/MS (M+l=282).

Example 4

7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline. To a roundbottom flask equipped with a magnetic stir bar was added7-Benzyloxy-6-methoxy-1H-quinolin-4-one (12.2 g, 43.3 mmol, 1.0 eq.),acetonitrile (150 ml), DMF (150 ml) and cesium carbonate (28.2 g, 86.5mmol, 2.0 eq). The mixture was stirred at room temperature for 30minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmol,1.1 eq) was added over a 10 minute period. After 2 hours the reactionwas complete at which time 75% of the MeCN and DMF was removed and theresulting solution was poured over into ice water. The solid wasfiltered and dried and further columned with a biotage system. Theeluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded7-Benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline as a palegreen solid (7.4 g, 41% yield). ¹H NMR (400 MHz, CDCl₃): 8.53 (d, 1H),8.42 (dd, 1H), 8.16 (m, 1H), 7.5 (m, 8H), 6.76 (d, 1H), 5.31 (s, 2H),3.92 (s, 3H); MS (EI) for C₂₃H₂₇FN₂O₅: 421 (MH⁺).

Example 5

4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol. To a round bottomflask equipped with a magnetic stir bar was added7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (2.9 g, 6.9mmol, 1.0 eq) and 33% HBr in acetic acid (30 ml). The mixture wasstirred at room temperature for 3 hours and diluted with ether to give apale white solid. The solid was filtered, washed with ether and dried toyield 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol as a palewhite solid (2.74 g, 97.5% yield). ¹H NMR (400 MHz, CDCl₃): 11.89 (bs,1H), 8.87 (d, 1H), 8.57 (d, 1H), 8.30 (d, 1H), 7.89 (m, 1H), 7.73 (s,1H), 7.55 (s, 1H), 4.03 (s, 3H); MS (EI) for C₁₆H₁₁FN₂O₅: 421 (M+H⁺).

Example 6

5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester. To a round bottom flask equipped with a magnetic stirbar was added 4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (2.74g, 6.7 mmol, 1.0 eq.), DMA (30 ml) and cesium carbonate (6.6 g, 20.2mmol, 3.0 eq). The mixture was stirred at room temperature for 30minutes at which time5-methanesulfonyloxymethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (2.6 g, 7.3 mmol, 1.1 eq) was added. The reaction washeated to 75° C. and allowed to stir overnight. After allowing thereaction to cool to room temperature the reaction was poured into water.The solid was filtered and was then dissolved in EtOAc and washed 2×water, 1× brine and dried over NaSO₄. The solvent was removed to yield5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester as a cream solid (3.7 g, 94% yield). ¹H NMR (400 MHz,CDCl₃): 8.55 (d, 1H), 8.15 (d, 1H), 8.09 (d, 1H), 7.32 (m, 8H), 6.52 (d,1H), 5.11 (d, 2H), 4.13 (d, 2H), 3.95 (s, 3H), 3.57 (m, 2H), 3.43 (m,2H), 2.93 (m, 3H), 2.16 (m, 2H), 1.39 (m, 2H); MS (EI) for C₃₂H₃₀FN₃O₇:588 (M+H⁺).

Example 7

4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline.To a round bottom flask equipped with a magnetic stir bar was added5-[4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-hexahydrocyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (2.5 g, 4.1 mmol, 1.0 eq), 33% HBr in acetic acid (5ml) and acetic acid (5 ml). The mixture was stirred at room temperaturefor 1 hour and diluted with EtOAc to give a pale orange solid. The solidwas filtered, washed with EtOAc and dried, giving4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline(2.1 g, 95% yield). ¹H NMR (400 MHz, CDCl₃): 8.83 (d, 1H), 8.32 (m, 2H),8.02 (s, 1H), 7.76 (t, 1H), 7.65 (s, 1H), 6.89 (d, 1H), 5.3 (d, 2H),4.11 (m, 3H), 3.26 (m, 4H), 2.95 (m, 2H), 2.68 (m, 3H), 2.36 (m, 2H),1.68 (m, 2H); MS (EI) for C₂₄H₂₄FN₃O₅: 454 (M+H⁺).

Example 8

4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline.To a round bottom flask equipped with a magnetic stir bar was added4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline(2.1 g, 3.9 mmol, 1.0 eq.) and acetonitrile/water 1:1 (5 ml, 5 ml). Thereaction mixture was then cooled to 0° C. and 37% solution offormaldehyde in water was added (0.2 g, 7.8 mmol, 2.0 eq). While keepingthe temperature at 0° C. Na(OAc)₃BH was added (4.4 g, 20.7 mmol, 3.0eq). After 1 hour the pH was adjusted to 10 and the aqueous wasextracted 2×DCM (100 ml). Removal of the DCM resulted in a white solid.The compound was further purified with a biotage system using an eluentEtOAc and 5% MeOH, affording4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydrocyclopenta[c]pyrrol-5-ylmethoxy)-quinoline(0.9 g, 50% yield).). ¹H NMR (400 MHz, CDCl₃): 8.57 (d, 1H), 8.14 (dd,1H), 8.12 (dd, 1H), 7.41 (s, 2H), 7.34 (t, 1H), 6.54 (d, 1H), 4.19 (d,2H), 4.01 (s, 3H), 2.61 (m, 4H), 2.43 (m, 1H), 2.33 (s, 3H), 2.11 (m,4H), 1.32 (m, 2H); MS (EI) for C₂₅H₂₆FN₃O₅: 468 (M+H⁺).

Example 9

3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamine.To a par hydrogenation reaction vessel was added4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinoline(0.800 g, 1.6 mmol, 1.0 eq.), DMF (50 ml), EtoAc (50 ml), MeOH (50 ml),TEA (5 ml) and 10% Pd/C (200 mg). The vessel was placed on the parhydrogenator at 35 psi overnight. The Pd was filtered and the solventremoved to give3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamineas an off yellow solid (0.78 g, 99% yield). ¹H NMR (400 MHz, CDCl₃):8.45 (d, 1H), 7.57 (s, 1H), 7.36 (s, 1H), 7.05 (t, 1H), 6.54 (m, 2H),6.39 (d, 1H), 4.16 (d, 2H), 4.01 (s, 3H), 3.81 (m, 3H), 2.61 (m, 3H),2.41 (m, 1H), 2.29 (s, 3H), 2.23 (m, 2H), 1.32 (m, 2H); MS (EI) forC₂₅H₂₈FN₃O₃: 438 (M+H⁺).

Example 10

1-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea.To a round bottom flask equipped with a magnetic stir bar was added3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamine(0.78 mg, 1.7 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) andphenyl-acetyl isothiocyanate (1.64 g, 9.2 mmol, 4.5 eq). The reactionmixture was stirred at room temperature overnight. After removal of thesolvent the product was purified with a biotage system using an eluentEtOAc and 4% TEA (2 L) then EtOAc, 4% TEA, 1% MeOH (1 L). The solventwas removed to give1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea(0.5 g, 50% yield). ¹H NMR (400 MHz, DMSO): 8.48 (d, 1H), 7.92 (dd, 1H),7.53 (s, 1H), 7.40 (m, 4H), 7.33 (d, 2H), 7.23 (m, 2H), 6.54 (d, 2H),6.39 (d, 1H), 4.21 (d, 2H), 4.02 (s, 3H), 3.81 (m, 3H), 2.87 (d, 2H),2.73 (m, 4H), 2.53 (m, 1H), 2.27 (m, 2H), 2.01 (s, 3H), 1.36 (m, 2H); MS(EI) for C₃₄H₃₅FN₄O₄S: 615 (M+H⁺).

Example 11

6-(6,7-Dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine.4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (1.00 g, 3.18mmol) was dissolved in AcOH (8.0 ml), to which was added NH₄SCN (486 mg,6.38 mmol) and the mixture cooled in an ice bath. Br₂ (0.33 ml, 6.42mmol) in AcOH (0.33 ml) was added dropwise with stirring. After additionwas complete, the reaction mixture was stirred at room temperature.After one hour, more NH₄SCN (1.0 g, 13.1 mmol) was added, followed bymore Br₂ (0.33 ml, 6.42 mmol) in AcOH (0.33 ml), dropwise with stirring.The reaction mixture was then heated to reflux for several minutes. Uponcooling to room temperature, solids were filtered and washed with AcOH,followed by H₂O. The volume of the filtrate was reduced in vacuo and thepH adjusted to pH 9-10 with 1.0N NaOH. The resulting solids werefiltered, washed with H₂O, and dried under high vacuum to give6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (568mg, 48%). ¹H-NMR (400 MHz, DMSO): 8.45 (d, 1H), 7.82 (d, 1H), 7.73 (brs, 2H), 7.53 (s, 1H), 7.38 (m, 2H), 6.44 (d, 1H), 3.94 (s, 6H). LC/MSCalcd for [M+H]⁺ 372.1, found 372.2

Example 12

N-[6-(6,7-Dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-phenyl-acetamide.6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (95mg, 0.25 mmol), Et₃N (0.10 ml, 0.72 mmol), phenylacetyl chloride (0.044ml, 0.33 mmol), and THF (1.0 ml) were combined and stirred at roomtemperature for 1 hr. Additional phenylacetyl chloride (0.044 ml, 0.33mmol) was added and the mixture heated to reflux for 1-2 hrs. Aftercooling to room temperature, the reaction mixture was diluted with 1:1AcCN:H₂O (1.0 ml) and the resulting solids filtered, washed with 1:1AcCN:H₂O and dried under high vacuum to giveN-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-phenyl-acetamide(72 mgs, 59%). ¹H-NMR (400 MHz, DMSO): 12.80 (s, 1H), 8.54 (d, 1H), 8.18(d, 1H), 7.91 (d, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.34 (m, 4H), 7.28(m, 1H), 6.60 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.86 (s, 2H). LC/MSCalcd for [M+H]⁺ 490.1, found 490.0.

Example 13

5-[4-(4-Amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester. 4-Amino-2-fluoro-phenol (1.53 g, 12.0 mmol) wasdissolved in dry DMF (30 ml) to which was added 60% NaH (774 mg, 19.3mmol). After the mixture was stirred at room temperature for severalminutes, a suspension of5-(4-chloro-6-methoxy-quinazolin-7-yloxymethyl)-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (4.70 g, 6.7 mmol) in dry DMF (40 ml) was added. Thereaction mixture was stirred at room temperature for 1-2 hrs, thendiluted with EtOAc and washed with sat'd NaHCO₃ (3×), H₂O (1×), sat'dNaCl (1×), dried (Na₂SO₄), and concentrated in vacuo to give crude5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (5.6 g, 100%) which was used in the next reactionwithout further purification. ¹H-NMR (400 MHz, DMSO): 8.50 (s, 1H), 7.48(s, 1H), 7.34 (m, 5H), 7.28 (m, 1H), 7.02 (t, 1H), 6.48 (dd, 1H), 6.40(dd, 1H), 5.40 (br s, 2H), 5.05 (s, 2H), 4.16 (d, 2H), 3.92 (s, 3H),3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H),1.30 (m, 2H). LC/MS Calcd for [M+H]⁺ 559.2, found 559.4.

Example 14

5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester. Phenylacetyl chloride (2.65 ml, 20.0 mmol) and AgSCN(4.92 g, 29.6 mmol) were combined in dry toluene (50 ml) and heated toreflux for 2 hrs. The reaction mixture was allowed to cool to roomtemperature, the solids were filtered through celite and the filtrateconcentrated in vacuo. The resulting oil was combined with5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (5.6 g, 10 mmol) in 1:1 EtOH:toluene (100 ml) and themixture stirred at room temperature for 1-2 hrs. The reaction mixturewas diluted with EtOAc and washed with sat'd NaHCO₃ (3×), H₂O (1×),sat'd NaCl (1×), dried (Na₂SO₄), and concentrated in vacuo. Theresulting oil was purified by flash chromatography (3:1 EtOAc:hexanes)to give5-{4-[2-fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydrocyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (3.61 g, 49%) as a dark brown foam. ¹H-NMR (400 MHz,DMSO): 12.44 (s, 1H), 11.80 (s, 1H), 8.54 (s, 1H), 7.90 (m, 1H), 7.53(s, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.34 (m, 7H), 7.28 (m, 3H), 5.05(s, 2H), 4.16 (d, 2H), 3.94 (s, 3H), 3.72 (s, 2H), 3.48 (m, 2H), 3.30(m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MSCalcd for [M+H]⁺ 736.2, found 736.0.

Example 15

1-{3-Fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea,dihydrobromide salt.5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylicacid benzyl ester (3.3 g, 4.5 mmol) was dissolved in AcOH (70 ml) towhich was added 33% HBr in AcOH (12 ml). The reaction mixture wasstirred at room temperature for 1 hr, diluted with Et₂O (1000 ml) andthe resulting solids filtered, washed with Et₂O, and dried under highvacuum to give the1-{3-fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea,dihydrobromide salt (3.4 g, 100%). ¹H-NMR (400 MHz, DMSO): 12.42 (s,1H), 11.80 (s, 1H), 8.84 (br s, 2H), 8.64 (s, 1H), 7.92 (m, 1H), 7.59(s, 1H), 7.49 (m, 2H), 7.41 (s, 1H), 7.33 (m, 4H), 7.27 (m, 1H), 4.17(d, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.17 (m, 2H), 3.10 (m, 2H), 2.83(m, 2H), 2.45 (m, 1H), 2.15 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for[M+H]⁺ 602.2, found 602.1.

Example 16

1-{3-Fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea.1-{3-Fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea,dihydrobromide salt (3.4 g, 4.5 mmol) was dissolved in a combination ofAcCN (100 ml), H₂O (30 ml), and AcOH (2.45 ml). Formaldehyde (37% inH₂O, 855 ml, 10.5 mmol) was added and the mixture cooled in an ice bath.Na(OAC)₃BH (2.99 g, 14.1 mmol) was added and the reaction mixture wasstirred at 0 C for 1 hr, followed by stirring at room temperature for 2hrs. The reaction mixture was neutralized with the addition of sat'dNaHCO₃ and then concentrated in vacuo. The resulting aqueous mixture wasextracted with CH₂Cl₂ (3×). The combined extractions were washed withsat'd NaHCO₃ (1×), sat'd NaCl (1×), dried (Na₂SO₄), and concentrated invacuo. The resulting residue was purified by flash chromatography (100%EtOAc, followed by 4% Et₃N in EtOAc) to give the free base of1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea(1.13 g, 40%). The free base was converted to the HCl salt by dissolvingthe free base in a mixture of 1:1 AcCN:H₂O containing 2-3 equivalents of1 N HCl and lyophilizing to give the HCl salt of1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thioureaas a white solid. ¹H-NMR (400 MHz, DMSO): 12.44 (s, 1H), 11.83 (s, 1H),10.24 (br s, 1H), 8.59 (s, 1H), 7.93 (m, 1H), 7.59 (s, 1H), 7.50 (m,2H), 7.42 (s, 1H), 7.36 (m, 4H), 7.30 (m, 1H), 4.20 (m, 2H), 3.95 (s,3H), 3.73 (s, 2H), 3.39 (m, 2H), 3.06 (m, 2H), 2.95-2.77 (m, 5H), 2.35(m, 1H), 2.15 (m, 2H), 1.45 (m, 2H). LC/MS Calcd for [M+H]⁺ 616.2, found616.2. Alternatively, the free base was converted to the acetate salt bydissolving the free base in a mixture of MeOH and CH₂Cl₂ to which wasadded 3 equivalents of acetic acid. The resulting mixture wasconcentrated in vacuo and the resulting residue lyophilized from 1:1AcCN:H₂O to give the acetate salt of1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thioureaas a white solid. ¹H-NMR (400 MHz, CDCl₃): d 12.45 (s, 1H), 8.65 (s,1H), 7.98 (dd, 1H), 7.50 (s, 1H), 7.40 (m, 4H), 7.29 (m, 4H), 4.17 (d,2H), 4.05 (s, 3H), 3.75 (s, 2H), 2.93 (m, 2H), 2.80 (m, 2H), 2.72 (m,2H), 2.53 (s, 3H), 2.47 (m, 1H), 2.25 (m, 2H), 2.02 (s, 3H), 1.35 (m,2H). LC/MS Calcd for [M+H]⁺ 616.2, found 616.2.

Example 17

(6,7-Dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine. Amixture of 4-chloro-6,7-dimethoxy-quinazoline (548 mg, 2.4 mmol),2-fluoro-4-nitro-phenylamine (392 mg, 2.5 mmol), AcCN (10 ml), andconc'd HCl (0.050 ml) was heated to reflux for several hrs. After thereaction mixture was allowed to cool to room temperature, the resultingsolids were filtered, washed with AcCN and air-dried to give(6,7-dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673mgs, 80%). ¹H-NMR (400 MHz, DMSO): 12.18 (br s, 1H), 8.91 (s, 1H), 8.45(s, 1H), 8.36 (dd, 1H), 8.24 (dd, 1H), 7.91 (dd, 1H), 7.44 (s, 1H), 4.04(s, 3H), 4.02 (s, 3H). LC/MS Calcd for [M+H]⁺ 345.1, found 345.4.

Example 18

N′-(6,7-Dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-1,4-diamine.(6,7-Dimethoxy-quinazolin-4-yl)-(2-fluoro-4-nitro-phenyl)-amine (673 mg,1.95 mmol) was dissolved in a combination of DMF (20 ml) and MeOH (20ml), to which was added 10% Pd/C (227 mg). The mixture was shaken underan atmosphere of H₂ on a Parr hydrogenator at 40 psi for 3 hrs. Thereaction mixture was filtered through celite and the filtrateconcentrated in vacuo. The resulting residue was triturated inEtOAc/Et₂O. The resulting solids were filtered, washed with Et₂O, anddried under vacuum to giveN¹-(6,7-dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-1,4-diamine (398 mg,65%) which was used in the next reaction without further purification.¹H-NMR (400 MHz, DMSO): 10.80 (br s, 1H), 10.30 (br s, 1H), 8.63 (s,1H), 8.15 (s, 1H), 7.33 (s, 1H), 7.15 (m, 1H), 6.45 (m, 1H), 3.96 (s,6H). LC/MS Calcd for [M+H]⁺ 315.1, found 315.4.

Example 19

1-[4-(6,7-Dimethoxy-quinazolin-4-ylamino)-3-fluoro-phenyl]-3-phenylacetyl-thiourea.Phenylacetyl chloride (0.18 ml, 1.4 mmol) and AgSCN (338 mg, 2.0 mmol)were combined in dry toluene (5 ml) and heated to reflux for 2 hrs. Thereaction mixture was allowed to cool to room temperature, the solidswere filtered through celite and the filtrate concentrated in vacuo. Theresulting oil was combined withN¹-(6,7-Dimethoxy-quinazolin-4-yl)-2-fluoro-benzene-1,4-diamine (398 mg,1.3 mmol) in 1:1:2 EtOH:toluene:MeOH (30 ml) and the mixture stirred atroom temperature overnight. The resulting solids were filtered andwashed with toluene, followed by hexanes. The solids weredissolved/suspended in a mixture of EtOAc/MeOH. Insoluble material wasfiltered and the filtrate concentrated in vacuo. The resulting solidswere once again dissolved/suspended in a mixture of EtOAc/MeOH. Insoluble material was filtered and the filtrate concentrated in vacuo togive1-[4-(6,7-dimethoxy-quinazolin-4-ylamino)-3-fluoro-phenyl]-3-phenylacetyl-thiourea(105 mg, 17%). ¹H-NMR (400 MHz, DMSO): 12.53 (s, 1H), 11.86 (s, 1H),11.44 (br s, 1H), 8.81 (s, 1H), 8.25 (s, 1H), 7.94 (dd, 1H), 7.54 (m,2H), 7.16 (m, 5H), 7.10 (m, 1H), 4.02 (s, 6H), 3.84 (s, 2H). LC/MS Calcdfor [M+H]⁺ 492.1, found 492.4.

Example 20

6,7-Dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline. To a round bottomflask equipped with a magnetic stir bar was added6,7-dimethoxy-1H-quinolin-4-one (1.8 g, 8.77 mmol, 1.0 eq.), anhydrousacetonitrile (90 mL) and Cs₂CO₃ (3.13 g, 9.65 mmole, 1.1 eq.). Thereaction mixture was stirred at room temperature for 5 minutes. Then,2-C₁₋₅-nitropyridine (1.53 g, 9.65 mmol, 1.1 eq.) was added. Thereaction mixture was stirred at room temperature for 16 hours. Thesolids were then filtered off and the filtrate was concentrated viarotary evaporation. The resulting material was taken up in EtOAc, andagain the solids were filtered off. The EtOAc filtrate was concentrated.Purification was done on Biotage with solvent system EtOAc 100%. Thecollected pure fractions were concentrated and dried on high vacuumovernight to give 6,7-dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline asa yellow foam solid (0.902 g, 31.4% yield). ¹H NMR (400 MHz, CDCl₃):9.08 (d, 1H), 8.74 (d, 1H), 8.60 (dd, 1H), 7.49 (s, 1H), 7.26 (d, 1H),7.16 (s, 1H), 7.07 (d, 1H), 4.06 (s, 3H), 3.95 (s, 3H); MS (EI) forC₁₆H₁₃N₃O₅: 328 (M+H⁺).

Example 21

6-(6,7-Dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine. To a round bottomflask equipped with a magnetic stir bar was added6,7-dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline (0.46 g, 1.41 mmol,1.0 eq.), and THF (10 mL), MeOH (4 mL), DMF (2 mL), and TEA (2 mL). The6,7-Dimethoxy-4-(5-nitro-pyridin-2-yloxy)-quinoline was dissolvedcompletely in the above solution mixture, and was flushed with nitrogenfor at least 5 minutes. The Pd/C (10% by weight) (0.090 g, 20% byweight) was then added. A balloon filled with H₂ was connected to theflask after the nitrogen was vacuumed out. The reaction mixture wasstirred at room temperature for 4 hours. The palladium was filtered outthrough Celite, and the filtrated was collected and concentrated viarotary evaporation. The resulting oil-like product was taken up into 5mL of water and 1 mL of acetonitrile and lyophilized to yield6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine as a light brownsolid (0.411 g, 98.1%). ¹H NMR (400 MHz, CDCl₃): 8.54 (d, 1H), 7.85 (d,1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.18 (dd, 1H), 6.96 (d, 1H), 6.61 (d,1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.73 (s, 2H); MS (EI) for C₁₆H₁₅N₃O₃:298 (M+H⁺).

Example 22

1-[6-(6,7-Dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-3-phenylacetyl-thiourea.To a round bottom flask equipped with a magnetic stir bar was added6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-ylamine (85 mg, 0.0285mmol, 1.0 eq.), and Phenyl-acetyl isothiocyanate (256 mg, 1.44 mmol, 5.0eq.) dissolved in EtOAc/MeOH 50:50 (2 mL). The reaction mixture wasstirred at room temperature for 12 hours, and the solvent was evaporatedvia rotary evaporation. Purification was done on Biotage with solventsystem 95% EtOAc, 4% TEA and 1% MeOH. The combined pure fractions wereconcentrated and dried under vacuum overnight to yield1-[6-(6,7-dimethoxy-quinolin-4-yloxy)-pyridin-3-yl]-3-phenylacetyl-thioureaas a light yellow solid (40.4 mg, 29.7%). ¹H NMR (400 MHz, CDCl₃): 8.65(d, 1H), 8.33 (d, 1H), 8.27 (dd, 1H), 7.35 (m, 7H), 7.15 (d, 1H), 6.92(d, 1H), 4.05 (s, 3H), 3.99 (s, 3H), 3.76 (s, 2H); MS (EI) forC₂₅H₂₂N₄O₄S: 475 (M+H⁺).

Example 23

N-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-phenethyl-oxalamide.To a solution of 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine(263 mg, 0.83 mmol) and Et₃N (0.223 ml, 1.67 mmol) in CH₂Cl₂ (10 mL) wasadded dropwise a solution of ethyl oxalyl chloride in CH₂Cl₂ (1 mL). Thestirring was continued for 0.5 h at rt. The reaction mixture was thenwashed with aqueous saturated NaHCO₃ and dried over NaSO₄. Removal ofthe solvent gave the crude oxamate, which was treated with neatphenethylamine (1.0 g, 8.3 mmol) at 80° C. for 3 h. Purification byflash column chromatography (hexanes:EtOAc=1:3) gaveN-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-N′-phenethyl-oxalamide(310 mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ 9.35 (br s, 1H), 8.70 (d, J=6.3Hz, 1H), 7.83 (dd, J=11.9, 2.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.43 (s, 1H),7.38-7.32 (m, 3H), 7.30-7.20 (m, 4H), 6.41 (d, J=5.3 Hz, 1H), 4.07 (s,3H), 4.05 (s, 3H), 3.67 (dt, J=7.0, 7.0 Hz, 2H), 2.92 (t, J=7.2 Hz, 2H).LC-MS: 490 [M+H]⁺

Example 24

N-{3-Fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide.To a flask containing7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (850 mg,2.0 mmol) was added 20 mL of 30% HBr in AcOH. The resulted solution wasstirred for 4 h at rt; at this time, a large amount of precipitateformed. The crude product was filtered, washed with Et₂O and dried inair, giving 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline(609 mg, 92% yield).

To a solution of the4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8mmol) in DMF (9 mL) was added K₂CO₃ (1.24 g, 9.0 mmol) andN-Boc-4-piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture wasthen stirred at 80° C. for 2.5 h. After it was cooled to rt, the mixturewas loaded directly to a Biotage column, and eluted with solvents(hexanes:EtOAc=1:3). The resulting product,4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester, was obtained as a solid (556 mg, 56%).

To a solution of4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (305 mg, 0.58 mmol) in CH₂Cl₂ (1 mL) was added 0.4mL of TFA. The reaction mixture was stirred for 1.5 h and the solventswere removed under reduced pressure. The crude product was treated withNaBH(OAc)₃ (381 mg, 1.80 mmol) and formaldehyde (0.5 mL, 37% in H₂O).The stirring was continued for 12 h. The reaction was quenched with sat.aqueous NaHCO₃. 15% NaOH was added until PH=14. The product wasextracted with EtOAc. Removal of the solvent in vacuo gave the crudeproduct,4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinoline,(240 mg, 93%), which was used directly in the next reaction.

To a solution of4-(2-Fluoro-4-nitro-phenoxy)-6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinoline(240 mg, 0.54 mmol) in EtOH (20 mL) was added 10% Pd/C (50 mg). Themixture was then hydrogenated on a Parr hydrogenator (40 psi) for 10 h.AcOH was added to dissolve the intermediate (mostly the hydroxylamine)and the hydrogenation was continued for additional 12 h. LC-MS was usedto monitor the reaction progress. The solvents were removed underreduced pressure and the resulting crude product of3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenylamine(about 220 mg) was used directly in the next reaction.

To a 0° C. solution of3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenylamine(66 mg, 0.13 mmol) and Et₃N (0.34 mL) in CH₂Cl₂ (6 mL) was added slowlyethyl oxalyl chloride (98 mg). The reaction mixture was stirred at rtfor 30 min, then diluted with CH₂Cl₂ and washed with sat. aqueousNaHCO₃. After dried over MgSO₄ and concentrated, the crude ethyl oxamatewas reacted with phenethylamine (80 mg, 0.64 mmol) at 80° C. for 2 h.Purification by HPLC gave product,N-{3-fluoro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-N′-phenethyl-oxalamide(52 mg, 68% yield). ¹H NMR (400 MHz) δ 9.38 (br s, 1H), 8.48 (d, J=5.2Hz, 1H), 7.83 (dd, J=11.7, 2.6 Hz, 1H), 7.59 (t, J=6.2 Hz, 1H), 7.55 (s,1H), 7.40-7.20 (8H), 6.39 (d, J=5.3 Hz, 1H), 4.06 (d, J=6.6 Hz, 2H),4.04 (s, 3H), 3.67 (q, J=6.8 Hz, 2H), 2.98 (br d, J=11.5 Hz, 2H), 2.92(t, J=7.0 Hz, 2H), 2.34 (s, 3H), 2.10-1.80 (m, 5H), 1.60-1.54 (m, 2H).

Example 25

1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid. The titlecompound was prepared based on a modified procedure of Shih and Rankin[Synthetic Communications, 1996, 26(4), 833-836]: To a mixture ofcyclopropane-1,1-dicarboxylic acid (21.2 g, 0.163 mol, 1.0 eq.) inanhydrous THF (200 mL) under nitrogen was added dropwise triethylamine(16.49 g, 0.163 mol, 1.0 eq.) with stirring for 30 minutes at 0° C.,followed by the addition of thionyl chloride (19.39 g, 0.163 mol, 1.0eq.) with stirring for another 30 minutes at 0° C. To the resultingmixture under nitrogen was added dropwise a solution of 4-fluoroaniline(19.92 g, 0.179 mol, 1.1 eq.) in anhydrous THF (100 mL) with stirringfor 1.5 hours at 0° C. The reaction mixture was diluted with ethylacetate and washed with 1N NaOH. The layers were separated, and theethyl acetate layer was concentrated in vacuo to give a brownish solid.The brownish solid was washed with small amount of cold ethyl acetate,filtered and dried under vacuum to yield1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid as a whitesolid (23.71 g, 65.18%). ¹H NMR (400 MHz, CD₃OD): 7.57-7.53 (m, 2H),7.05-7.00 (m, 2H) 1.46-1.43 (m, 2H), 1.40-1.37 (m, 2H).

Example 26

1-(4-Fluoro-phenylcarbamoyl)-cyclobutanecarboxylic acid. To a mixture ofcyclobutane-1,1-dicarboxylic acid (10.0 g, 69.4 mmol, 1.0 eq.) inanhydrous THF (100 mL) under nitrogen was added dropwise triethylamine(7.02 g, 69.4 mmol, 1.0 eq.) with stirring for 30 minutes at 0° C.,followed by the addition of thionyl chloride (8.25 g, 69.4 mmol, 1.0eq.) with stirring for another 30 minutes at 0° C. To the resultingmixture under nitrogen was added dropwise a solution of 4-fluoroaniline(8.48 g, 76.3 mmol, 1.1 eq.) in anhydrous THF (50 mL) with stirring for1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetateand extracted with 2N NaOH. The aqueous phase was titrated with 2N HClto pH 1-2 and then extracted with ethyl acetate. The organic phase wasdried with sodium sulfate and concentrated in vacuo to give1-(4-fluoro-phenylcarbamoyl)-cyclobutanecarboxylic acid as a light pinksolid (5.75 g, 34.9%). ¹H NMR (400 MHz, CDCl₃ w/5 drop CD₃OD): 7.53-7.48(m, 2H), 7.06-7.00 (m, 2H), 2.81-2.63 (m, 4H), 2.14-2.02 (m, 2H).

Example 27

1-Benzylcarbamoyl-cyclopropanecarboxylic acid. The title compound wasprepared based on a modified procedure of Shih and Rankin [SyntheticCommunications, 1996, 26(4), 833-836]: To a mixture ofcyclopropane-1,1-dicarboxylic acid (5.0 g, 38.4 mmol, 1.0 eq.) inanhydrous THF (50 mL) under nitrogen was added dropwise triethylamine(3.89 g, 38.4 mmol, 1.0 eq.) with stirring for 30 minutes at 0° C.,followed by the addition of thionyl chloride (4.57 g, 38.4 mmol, 1.0eq.) with stirring for another 30 minutes at 0° C. To the resultingmixture under nitrogen was added dropwise a solution of benzylamine 5(4.53 g, 42.3 mmol, 1.1 eq.) in anhydrous THF (25 mL) with stirring for1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetateand extracted with 2N NaOH (to pH 10). The aqueous phase was titratedwith 2N HCl to pH 1-2 and then extracted with ethyl acetate. The organicphase was dried with sodium sulfate and concentrated in vacuo to give1-Benzylcarbamoyl-cyclopropanecarboxylic acid as a white solid (4.39 g,52.15%). ¹H NMR (400 MHz, CDCl₃): 8.44 (br s, 1H), 7.37-7.33 (m, 2H),7.32-7.26 (m, 3H), 1.82-1.70 (m, 4H).

Example 28

1-Phenylcarbamoyl-cyclopropanecarboxylic acid. To a mixture ofcyclopropane-1,1-dicarboxylic acid (5.29 g, 40.7 mmol, 1.0 eq.) inanhydrous THF (50 mL) under nitrogen was added dropwise triethylamine(4.12 g, 40.7 mmol, 1.0 eq.) with stirring for 30 minutes at 0° C.,followed by the addition of thionyl chloride (4.84 g, 40.7 mmol, 1.0eq.) with stirring for another 30 minutes at 0° C. To the resultingmixture under nitrogen was added dropwise a solution of phenylamine 9(4.17 g, 44.8 mmol, 1.1 eq.) in anhydrous THF (25 mL) with stirring for1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetateand extracted with 2N NaOH (to pH>10). The aqueous phase was titratedwith 2N HCl to pH 1-2 and then extracted with ethyl acetate. The organicphase was dried with sodium sulfate and concentrated in vacuo to give1-phenylcarbamoyl-cyclopropanecarboxylic acid as a white solid (5.08 g,60.8%). ¹H NMR (400 MHz, CDCl₃): 10.50 (br s, 1H), 7.56-7.54 (m, 2H),7.35-7.31 (m, 2H), 7.15-7.10 (m, 1H), 1.94-1.91 (m, 2H), 1.82-1.79 (m,2H).

Example 29

7-Benzyloxy-4-chloro-6-methoxy-quinoline. Dry DMF (8.0 ml, 103 mmol) wasdissolved in dry CHCl₃ (40 ml) and cooled in an ice bath. Oxalylchloride (9.0 ml, 105 mmol) in CH₂Cl₂ (10 ml) was added dropwise withstirring at 0° C. When the bubbling had ceased, this solution was addedslowly to an ice-cold solution of7-benzyloxy-6-methoxy-3H-quinazolin-4-one (10.0 g, 35.4 mmol) in dryCHCl₃ (60 ml) and the mixture was then heated to reflux for 2-3 hrs.After cooling to room temperature, H₂O (100 ml) was added and the phaseswere separated. The aqueous phase was further extracted with CHCl₃ (2×).The combined CHCl₃ extractions were washed with sat'd NaCl (1×), dried(Na₂SO₄) and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (1:1 hexanes:EtOAc, followed by 100% EtOAc) togive 7-benzyloxy-4-chloro-6-methoxy-quinoline (5.11 g, 48%). LC/MS Calcdfor [M+H]⁺ 301.1, found 301.1.

Example 30

Cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide.To a solution of cyclopropane-1,1-dicarboxylic acid[4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide (1.18 g, 2.0 mmol) in EtOH (20 mL) was added1,4-cyclohexadiene (2.0 mL, 20 mmol) and 10% Pd/C (300 mg). The reactionmixture was then heated to reflux and the stirring was continued for 2h. It was cooled to room temperature, filtered through celite and washedwith MeOH. The MeOH solution was then concentrated under reducedpressure. The residue was taken into EtOAc (200 mL). The EtOAc solutionwas washed with water, and dried over Na₂SO₄. Removal of the solventunder reduced pressure gave 900 mg (89%) of the crude product (90%purity by analytical HPLC), which was used in the next reaction withoutfurther purification.

Example 31

N-(4-{[7-{[2-(Diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.To a mixture of cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide(186 mg, 0.36 mmol) in CH₂Cl₂ (10 mL) was added 2-(diethylamino)ethanol(63 mg, 0.54 mmol), and PPh₃ (141 mg, 0.54 mmol). DIAD (109 mg, 0.54mmol) was then added as a CH₂Cl₂ (1 mL) solution. The resulted solutionwas stirred at room temperature for 2 h and the solvent was removedunder reduced pressure. To the residue was added 1 N HCl (50 mL), and itwas washed with EtOAc (50 mL×2). The aqueous phase was basified byadding 15% NaOH aqueous solution until pH=11-13, and then extracted withether (50 mL×2). The combined organic layer was dried (MgSO₄), andconcentrated in vacuo. The residue was purified on preparative HPLC togiveN-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide(74 mg, 34%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.40(br s, 1H), 10.02 (br s, 1H), 8.47 (d, J=5.2 Hz, 1H), 7.91 (br d, J=13.9Hz, 1H), 7.54-7.52 (m, 2H), 7.55-7.50 (m, 1H), 7.52 (s, 1H), 7.50-7.40(m, 1H), 7.41 (s, 1H), 7.16 (br t, J=8.7 Hz, 2H), 6.41 (br d, J=4.7 Hz,1H), 4.18 (t, J=6.0 Hz, 2H), 3.94 (s, 3H), 2.87 (br t, J=6.3 Hz, 2H),2.59 (q, J=7.1 Hz, 4H), 1.47 (br s, 4H), 1.00 (t, J=7.0 Hz, 6H).

Example 32

1-(4-Benzyloxy-3-methoxyphenyl)ethanone. A solution of4-hydroxy-3-methoxyacetophenone (40 g, 240 mmol), benzyl bromide (31.4mL, 260 mmol) and potassium carbonate (99.6 g, 360 mmol) in DMF (800 mL)was heated to 40° C. overnight. The solution was cooled to roomtemperature, poured over ice and the resultant solid was filtered. Thismaterial was washed with water and dried to give1-(4-benzyloxy-3-methoxyphenyl)ethanone (61 g, 99%).

1-(4-Benzyloxy-5-methoxy-2-nitrophenyl)ethanone. A stirred solution of1-(4-benzyloxy-3-methoxyphenyl)ethanone (51.3 g, 200 mmol) indichloromethane (750 mL) was cooled to 0° C. Nitric acid (90%, 14 mL,300 mmol) was added dropwise to the cooled solution over 20 min.Sulfuric acid (96.2%, 16.3 mL, 300 mmol) was then added dropwise over 40min at 0° C. Additional nitric acid (9.4 mL, 200 mmol) was addeddropwise over 20 min. The reaction mixture was washed with water (3×200mL), and saturated sodium bicarbonate (4×200 mL, or until neutral). Theorganic layer was dried over Na₂SO₄ and concentrated. The crude mixturewas recrystallized from DMF to give1-(4-benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 60%). ¹H NMR (400MHz, CDCl₃): δ 7.65 (s, 1H), 7.45-7.33 (m, 5H), 6.74 (s, 1H), 5.21 (s,2H), 3.97 (s, 3H), 2.49 (s, 3H).

1-(2-Amino-4-benzyloxy-5-methoxyphenyl)ethanone. A mixture of ironpowder (27 g, 0.48 g atoms), ammonium formate (31 g, 500 mmol),1-(4-benzyloxy-5-methoxy-2-nitrophenyl)ethanone (36 g, 120 mmol),toluene (500 mL) and water (500 mL) was heated to reflux overnight. Themixture was filtered through celite and washed with ethyl acetate. Thecombined organic layers were washed with water and brine. The organiclayer was dried over Na₂SO₄ and concentrated to afford1-(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 90%). ¹H NMR(CDCl₃): δ 7.41-7.30 (m, 5H), 7.13 (s, 1H), 6.16 (br s, 2H), 6.10 (s,1H), 5.13 (s, 2H), 3.83 (s, 3H), 2.51 (s, 3H). LC/MS (M+H=272).

7-Benzyloxy-6-methoxyquinolin-4-ol. Sodium ethoxide (74.8 g, 1.1 mol)was added to a solution of1-(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 108 mmol) inDME (700 mL) and stirred for 30 min. Ethyl formate (44 mL, 540 mmol) wasadded and the mixture was stirred overnight (in case of incompletereaction, additional sodium ethoxide can be added and the reactionmonitored by LC/MS). After the reaction was complete, the mixture wasdiluted with water (40 mL) and acidified to neutral pH with 1M HCl. Thesolid was filtered, washed with water and dried to afford7-benzyloxy-6-methoxyquinolin-4-ol (22 g, 72%). ¹H NMR (400 MHz, CDCl₃):δ 10.7 (br s, 1H), 7.70 (s, 1H), 7.49-7.46 (t, 1H), 7.43-7.41 (br d,2H), 7.37-7.33 (t, 2H), 7.30-7.28 (d, 1H), 6.84 (s, 1H), 6.21-6.19 (d,1H), 5.21 (s, 2H), 3.96 (s, 3H). LC/MS (M+H=282).

7-Benzyloxy-4-chloro-6-methoxyquinoline. Phosphorus oxychloride (300 mL)was added to 7-benzyloxy-6-methoxyquinolin-4-ol (40 g, 140 mmol) and themixture heated to reflux for 2 h. The mixture was carefully poured intoa mixture of ice and sodium carbonate. The solution was adjusted to pH 8with the addition of solid sodium bicarbonate and stirred at roomtemperature overnight. The solid was filtered and washed with water anddried to give 7-benzyloxy-4-chloro-6-methoxyquinoline as a pale brownsolid (40.2 g, 95%). ¹H NMR (400 MHz, d₆-DMSO): δ 8.61 (s, 1H),7.57-7.37 (m, 8H), 5.32 (s, 2H), 3.98 (s, 3H); ¹³C NMR (100 MHz,d₆-DMSO): δ 152.4, 151.5, 148.5, 146.2, 139.6, 137.0, 129.2, 128.8,121.7, 120.4, 110.1, 101.9, 70.8, 56.5; IR (cm⁻¹): 2359, 2341, 1506,1456, 1435, 1252, 1227, 1146, 999, 845, 752, 698, 667; LC/MS (M+H=300).

Example 33

Trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester.To a dry 2 L RBF containing 7-benzyloxy-6-methoxyquinolin-4-ol (75.3 g,267 mmol) was added DCM (1 L), 4-dimethylaminopyridine (3.28 g, 26.8mmol) and 2,6-lutidine (62 mL, 534 mmol). The mixture was cooled to −20°C. by controlled addition of dry ice to an acetone bath.Trifluoromethanesulfonyl chloride (37 mL, 350 mmol) was added dropwiseto the cooled solution with magnetic stirring over 25 minutes. Afteraddition was complete, the mixture was stirred in bath for 20 minutes,then at room temperature for 3 hours. LCMS indicated reactioncompletion. The reaction mixture was concentrated in vacuo and placedunder high vacuum to remove residual 2,6-lutidine. To the resultingbrown solids was added methanol (3.5 L). The resulting slurry wasstirred with mechanical stirrer for 30 min before adding water (1.5 L).The solids were isolated by filtration, followed by a water wash. Theresulting solid was dried under high vacuum overnight yieldingtrifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl esteras a light brown solid (92.2 g, 83.8%). ¹H NMR (400 MHz, DMSO, d₆): δ8.82 (d, 1H), 7.67 (s, 1H), 7.59 (d, 1H), 7.54-7.52 (m, 2H), 7.46-7.42(m, 2H), 7.39-7.36 (m, 1H), 7.23 (s, 1H), 5.35 (s, 2H), 3.97 (s, 3H).LC/MS: M+H=414.

Example 34

Trifluoromethanesulfonic acid 6,7-dimethoxyquinolin-4-yl ester from6,7-Dimethoxy-quinolin-4-ol. To a dry 1 L RBF containing6,7-dimethoxy-quinolin-4-ol (20.9 g, 102 mmol), which can be preparedaccording to the procedure of Riegel, B. (J. Amer. Chem. Soc. 1946, 68,1264), was added DCM (500 mL), 4-dimethylaminopyridine (1.24 g, 10 mmol)and 2,6-lutidine (24 mL, 204 mmol). The mixture was vigorously stirredat RT. Trifluoromethanesulfonyl chloride (14 mL, 132 mmol) was addeddropwise to the solution. After addition was complete, the mixture wasstirred ice bath for 2 to 3 hrs. On LC/MS indicating the reactioncompletion, the reaction mixture was concentrated in vacuo and placedunder high vacuum to remove residual 2,6-lutidine. To the resultingbrown solids was added methanol (250 mL). The resulting slurry wasstirred for 30 min before adding water (1 L). The solids were isolatedby filtration, followed by a water wash. The resulting solid was driedunder high vacuum overnight yielding trifluoromethanesulfonic acid6,7-dimethoxy-quinolin-4-yl ester as a light brown solid (27 g, 80%). ¹HNMR (400 MHz, DMSO, d₆): δ 8.82 (d, 1H), 7.59 (m, 2H), 7.20 (s, 1H),3.97 (d, 6H). LC/MS: M+H=338.

Example 35

1-Benzyloxy-2-fluoro-4-nitrobenzene. A solution of2-fluoro-4-nitrophenol (50.0 g, 318 mmol), benzyl bromide (42 mL, 350mmol) and potassium carbonate (66.0 g, 478 mmol) in DMF (200 mL) washeated to 40° C. overnight. The solution was cooled to room temperature,poured over ice and the resultant solid was filtered. This material waswashed with water and dried to give 1-benzyloxy-2-fluoro-4-nitrobenzene(75.0 g, 95%). ¹H NMR (400 MHz, d₆-DMSO): δ 8.19-8.11 (m, 2H), 7.53-7.37(m, 6H), 5.36 (s, 2H); ¹³C NMR (100 MHz, d₆-DMSO): δ 152.8, 152.4,149.9, 140.9, 136.1, 129.3, 129.1, 128.7, 122.0, 115.2, 112.8, 112.6,71.6; IR (cm⁻¹): 1499, 1346, 1279, 1211, 1142, 1072, 986, 885, 812, 789,754, 742, 700, 648, 577.

4-Benzyloxy-3-fluoroaniline. A mixture of iron powder (45.2 g, 0.809 gatoms), ammonium formate (53.6 g, 0.850 mol),1-benzyloxy-2-fluoro-4-nitrobenzene (50.0 g, 0.200 mol), toluene (400mL) and water (400 mL) was heated to reflux overnight. The mixture wasfiltered through Celite and washed with hot ethyl acetate. The combinedorganic layers were washed with water and brine, then dried over sodiumsulfate and concentrated to afford 4-benzyloxy-3-fluoroaniline (44 g,100%). ¹H NMR (400 MHz, d₆-DMSO): δ 7.43-7.26 (m, 5H), 6.90 (dd, 1H),6.49 (dd, 1H), 6.34 (m, 1H), 4.99 (br s, 2H), 4.98 (s, 2H); ¹³C NMR (100MHz, d₆-DMSO): 6171.1, 155.1, 152.7, 144.9, 138.0, 137.2, 129.6, 129.0,128.5, 118.9, 110.0, 102.9, 72.5; IR (cm⁻¹): 1510, 1454, 1277, 1215,1126, 1007, 957, 843, 800, 789, 739, 694, 604; LC/MS (M+H=218).

Ethyl [(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate. Ethyl oxalylchloride (44 mL, 390 mmol) was added to a solution of4-benzyloxy-3-fluoroaniline (44 g, 180 mmol) in diisopropylethylamine(69 mL, 400 mmol) and stirred at room temperature for 15 min. Themixture was extracted with dichloromethane and washed with water andbrine. The organic layer was dried over sodium sulfate and concentratedto afford ethyl [(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate (58.4 g,100%). ¹H NMR (400 MHz, d₆-DMSO): δ 10.87 (s, 1H), 7.73 (d, 1H), 7.69(d, 1H), 7.53 (d, 1H), 7.46-7.40 (m, 4H), 5.17 (s, 2H), 4.31 (q, 2H),1.31 (t, 3H); IR (cm⁻¹): 1732, 1705, 1558, 1541, 1508, 1456, 1273, 1186,1167, 1101, 999, 858, 741, 694; LC/MS (M+H=318).

N-(4-Benzyloxy-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide.Phenethyl-amine (33 mL, 520 mmol) was added to ethyl[(4-benzyloxy-3-fluorophenyl)amino](oxo)acetate (81 g, 260 mmol) and themixture was sonicated at room temperature for 30 min. The resultingsolid was filtered, washed with water and dried to giveN-(4-benzyloxy-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide (100 g,99%). ¹H NMR (400 MHz, d₆-DMSO): δ 10.72 (br s, 1H), 9.05 (m, 1H), 8.78(m, 1H), 7.77 (m, 1H), 7.59 (m, 1H), 7.46-7.19 (m, 8H), 5.16 (m, 2H),3.45 (m, 2H), 2.83 (m, 2H); IR (cm⁻¹): 2980, 2883, 1653, 1522, 1506,1441, 1385, 1221, 1122, 951, 808, 746, 696, 584; LC/MS (M+H=393).

N-(3-Fluoro-4-hydroxyphenyl)-N′-(2-phenylethyl)ethanediamide. A mixtureof N-(4-benzyloxy-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide (40 g,100 mmol) and 38% hydrobromic acid in acetic acid (250 mL) was stirredat room temperature overnight. The resulting solid was filtered, washedwith water and dried to giveN-(3-fluoro-4-hydroxyphenyl)-N′-(2-phenylethyl)ethanediamide as aslightly yellow solid (30.6 g, 99% yield). ¹H NMR (400 MHz, d₆-DMSO): δ10.60 (s, 1H), 9.02 (t, 1H), 7.70 (d, 1H), 7.47 (d, 1H), 7.32-7.20 (m,3H), 6.91 (t, 1H), 3.43 (m, 2H), 2.81 (m, 2H); ¹³C NMR (100 MHz,d₆-DMSO): δ 160.5, 158.8, 152.0, 149.6, 142.2, 139.8, 130.3, 129.3,129.0, 126.8, 118.1, 117.4, 109.6, 109.3 IR (cm⁻¹): 3279, 1653, 1518,1456, 1279, 1190, 742, 696, 584; LC/MS (M+H=303).

Example 36

1-Benzyloxy-2-fluoro-4-nitro-benzene. To a slurry of sodium hydride (60%dispersion is oil, 693 mmol, 27.7 g) and dimethylacetamide (600 ml) wasadded benzyl alcohol (462 mmol, 48 ml) dropwise with stirring under N₂.The mixture was stirred for 1 hour at RT and then cooled to 0° C.3,4-Difluoronitrobenzene (508 mmol, 56.2 ml) was added to the cooledsolution and stirred for 1 hour. Reaction mixture poured onto saturatedammonium chloride solution (800 ml) and stirred for 30 minutes, filteredand washed with water. The solid was stirred in ethyl acetate (500 mL),and filtered to give 54 g of product. The ethyl acetate filtrate, afterconcentrated in vacuo, was triturated with diethyl ether (500 mL),sonicated for 2 hours, and filtered to give another 30 g of product. Theether layer was concentrated and column purified using 5% EtOAc/hexanesas eluent to gave additional 15 g of product. The total yield of1-benzyloxy-2-fluoro-4-nitro-benzene was 95 g (83%). (Note: the productcontains ca. 5% of 3,4-Bis-benzyloxy-nitrobenzene, which is carried intothe next step without further purification.) ¹H NMR (400 MHz, CDCl₃): δ8.04-8.00 (m, 2H), 7.43-7.37 (m, 5H), 7.08 (t, 1H), 5.26 (s, 2H).

4-Benzyloxy-3-fluoro-phenylamine. A mixture of1-benzyloxy-2-fluoro-4-nitro-benzene (44 g, 178 mmol), toluene (400 ml),ammonium formate (35 g), iron (30 g), and water (400 ml) was heated toreflux with stirring overnight. The reaction mixture was filteredthrough celite and washed with ethyl acetate (400 ml). The organic layerwas separated and washed with brine (300 ml), dried over sodium sulfateand concentrated to give 4-benzyloxy-3-fluoro-phenylamine as an oil(33.7 g, 87%). ¹H NMR (400 MHz, CDCl₃): δ 7.41-7.29 (m, 5H), 6.79 (t,1H), 6.45 (dd, 1H), 6.14 (dd, 1H), 5.02 (s, 2H), 3.50 (s, 2H). LC/MS:(M+1) 218.

Cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-3-fluoro-phenyl)-amide(4-fluoro-phenyl)-amide. To a stirred mixture of4-benzyloxy-3-fluoro-phenylamine (155.3 mmol, 33.7 g),1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (170.8 mmol,38.13 g) and anhydrous dichloromethane (600 ml) was added EDCI (233.9mmol, 44.7 g) in portions. After stirring at RT for 1 hr, the reactionmixture was diluted with saturated sodium bicarbonate (400 ml) andstirred for 30 minutes. The precipitate was filtered and air dried togive the 1^(st) crop of product. The biphasic filtrate was separated,and the organic phase was washed with brine (300 ml), dried over sodiumsulfate, and concentrated. The residue was taken up in DCM (100 ml),stirred for 15 minutes, and filtered to give a 2^(nd) crop of product.The combined yield of cyclopropane-1,1-dicarboxylic acid(4-benzyloxy-3-fluoro-phenyl)-amide (4-fluoro-phenyl)-amide was 64.5 g(98%). ¹H NMR (400 MHz, CDCl₃): δ 8.92 (br s, 1H), 8.88 (br s, 1H),7.50-7.32 (m, 8H), 7.06-7.02 (m, 3H), 6.97-6.92 (t, 1H), 5.13 (s, 2H),1.65 (s, 4H). LC/MS: (M+1) 423.

Cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide(4-fluoro-phenyl)-amide. A mixture of cyclopropane-1,1-dicarboxylic acid(4-benzyloxy-3-fluoro-phenyl)-amide (4-fluoro-phenyl)-amide (152.8 mmol,64.5), ethanol (800 ml), cyclohexadiene (764 mmol, 71 ml), and 10% Pd/C(2 g) was refluxed for 2 hours. Reaction mixture cooled and filteredthrough celite and washed with methanol. The combined filtrate wasconcentrated and stirred in 10% EtOAc/ether (350 ml). The resultingprecipitate was filtered and washed with ether to give a 1^(st) crop ofproduct. The filtrate was concentrated and stirred in DCM (150 ml) togive another precipitate, which was then filtered to give a 2^(nd) cropof product. The combined yield of cyclopropane-1,1-dicarboxylic acid(3-fluoro-4-hydroxy-phenyl)-amide (4-fluoro-phenyl)-amide was 43 g (85%)in 95% purity by HPLC (UV @254 nm). ¹H NMR (400 MHz, DMSO-D6): δ 10.07(br s, 1H), 9.92 (br s, 1H), 9.64 (br s, 1H), 7.64-7.60 (m, 2H),7.55-7.51 (m, 1H), 7.17-7.12 (m, 3H), 6.89-6.84 (t, 1H), 1.43 (s, 4H).LC/MS: (M+1) 333.

Example 37

Cyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide(4-fluoro-phenyl)-amide. To a 0° C. suspension of 4-benzyloxyanilinehydrochloride (47.0 g, 200 mmol) and1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (49.1 g, 220mmol) in CH₂Cl₂ (400 mL) was added EDCI (38.2 g, 200 mmol). Stirring wascontinued at rt for 2-4 h until the reaction was complete. CH₂Cl₂ wasremoved under reduced pressure. H₂O (300 mL) and MeOH (200 mL) wereadded, and the resulting mixture was stirred at rt for 30 min. Afterfiltration and wash with H₂O, the solid was transferred to another flaskcontaining 300 mL of sat. aqueous NaHCO₃ solution. The mixture wasstirred for another 30 min. The solid was filtered, washed with water,and dried over night on a lyophilizer, affordingcyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide(4-fluoro-phenyl)-amide (75.8 g, 95% yield) as an off-white solid.

Cyclopropane-1,1-dicarboxylic acid (4-fluoro-phenyl)-amide(4-hydroxy-phenyl)-amide. To a refluxing mixture ofcyclopropane-1,1-dicarboxylic acid (4-benzyloxy-phenyl)-amide(4-fluoro-phenyl)-amide (46 g, 113 mmol), 10% Pd/C (2 g) in EtOH (400mL) was added dropwise 1,4-cyclohexadiene (62.7 mL, 678 mmol). Stirringwas continued for 2-5 h until the reaction was complete. The mixture wascooled to rt, filtered through celite, and washed with EtOH. Thesolution was then concentrated under reduced pressure. To the flaskcontaining the crude product was added CHCl₃ (200 mL). The resultingsuspension was stirred for 15 min at rt. The solid was filtered, anddried in the air to give cyclopropane-1,1-dicarboxylic acid(4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (34.4 g, 95%, yield).

Example 38

Alternate Synthesis of Cyclopropane-1,1-dicarboxylic acid(4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide. To a solution of4-aminophenol (2.93 g, 26.9 mmol) and1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (5.00 g, 22.4mmol) in DMA (30 mL) was added EDCI (5.15 g, 26.9 mmol). The mixture wasstirred vigorously until the reaction was complete (˜3 h). With vigorousstirring, the reaction mixture was then poured into a flask containingsat. aqueous NaHCO₃ solution (200 mL). The stirring was continued for 1h. The resulting suspension was then filtered. The solid was washed withwater (50 mL), chloroform (50 mL) and dried under vacuum, affording1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (6.22 g, 88%yield) as a powder (>95% purity by HPLC and ¹H NMR).

Example 39

N-{4-[(7-Benzyloxy-6-methoxyquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(2-phenylethyl)ethanediamide.A mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline (30 g, 100 mmol),N-(3-fluoro-4-hydroxyphenyl)-N′-(2-phenylethyl)ethanediamide (32 g, 106mmol), DMAP (125 g, 1.02 mol) and bromobenzene (500 mL) was heated toreflux for 6 h. The mixture was cooled to room temperature and thebromobenzene was removed under reduced pressure. Methanol (500 mL) wasadded to the residue and the mixture was stirred at room temperature for2 h. The resulting solid was filtered, washed with methanol and dried togiveN-{4-[(7-benzyloxy-6-methoxyquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(2-phenylethyl)ethanediamide(34 g, 61%). ¹H NMR (400 MHz, d₆-DMSO): δ 11.05 (s, 1H), 9.15 (s, 1H),8.47 (d, 1H), 8.05 (d, 1H), 7.84 (d, 1H), 7.56-6.36 (m, 13H), 6.46 (d,1H), 5.32 (s, 2H), 3.97 (s, 3H), 3.47 (q, 2H), 2.86 (t, 2H); ¹³C NMR(100 MHz, d₆-DMSO): δ 160.5, 160.2, 159.9, 159.5, 155.2, 152.7, 152.2,150.3, 149.6, 146.9, 139.7, 137.4, 137.3, 137.2, 137.1, 129.3, 129.2,129.1, 129.0, 128.9, 128.7, 128.6, 126.9, 124.8, 117.9, 115.3, 109.9,102.8, 99.8, 70.6, 56.5, 41.3, 35.2; IR (cm⁻¹): 1657, 1510, 1481, 1433,1416, 1352, 1310, 1252, 1215, 1609, 986, 891, 868, 850, 742, 696; LC/MS(M+H=566).

Example 40

N-{3-Fluoro-4-[(7-hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide.To a solution ofN-{4-[(7-benzyloxy-6-methoxyquinolin-4-yl)oxy]-3-fluorophenyl}-N′-(2-phenylethyl)ethanediamide(32 g, 56 mmol) in methanol (200 mL), DMF (100 mL), dichloromethane (100mL), ethyl acetate (100 mL) and acetic acid (5 mL) was added palladiumhydroxide (4.2 g) and the mixture was shaken on a Parr hydrogenatorunder a hydrogen pressure of 45 psi for 4 h. The resulting suspensionwas filtered through celite and the solid residue was washed withboiling dichloromethane (2 L) and acetone (2 L). The combined filtrateswere evaporated to yieldN-{3-fluoro-4-[(7-hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamideas an off-white solid (25.6 g, 95%). ¹H NMR (400 MHz, d₆-DMSO): δ 11.06(s, 1H), 10.25 (br s, 1H), 9.12 (t, 1H), 8.40 (d, 1H), 8.01 (dd, 1H),7.50-7.44 (m, 2H), 7.31-7.23 (m, 6H), 6.39 (d, 1H), 3.95 (s, 3H), 2.85(t, 2H), 2.50 (m, 2H); IR (cm⁻¹): 1666, 1624, 1585, 1520, 1481, 1427,1377, 1256, 1211, 1194, 1022, 880, 850, 839, 802, 750, 700; LC/MS(M+H=476).

Example 41

N-(3-Fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N′-(2-phenylethyl)ethanediamide.A solution ofN-{3-fluoro-4-[(7-hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide(25.6 g, 54 mmol), N-(3-chloropropyl)morpholine hydrochloride (11.7 g,592 mmol) and potassium carbonate (16.6 g, 120 mmol) in DMF (300 mL) washeated to 80° C. overnight. Upon cooling, a majority of the DMF (250 mL)was removed on a rotary evaporator, 5% aqueous LiCl (300 mL) was addedand the mixture was sonicated at room temperature. The solid wasfiltered, suspended in 1N HCl and washed with ethyl acetate (2×300 mL).The solution was adjusted to pH 14 using 2N sodium hydroxide andsubsequently extracted with dichloromethane (3×200 mL). The organiclayer was dried over sodium sulfate, filtered and evaporated to giveN-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N′-(2-phenylethyl)ethanediamideas a yellow solid (24 g, 74%). ¹H NMR (400 MHz, CDCl₃): δ 9.37 (s, 1H),8.46 (d, 1H), 7.81 (dd, 1H), 7.57 (t, 1H), 7.53 (s, 1H), 7.42 (s, 2H),7.34-7.20 (m, 6H), 6.39 (d, 1H), 4.27 (t, 2H), 4.03 (s, 3H), 3.71 (m,4H), 3.65 (q, 2H), 2.91 (t, 2H), 2.56 (br s, 4H), 2.13 (m, 2H); ¹³C NMR(100 MHz, d₆-DMSO): δ 160.1, 160.0, 159.5, 155.2, 152.7, 152.6, 150.2,149.5, 147.1, 139.7, 137.3, 137.1, 129.3, 129.1, 126.9, 124.8, 117.9,115.1, 109.2, 102.7, 99.6, 67.4, 66.9, 56.5, 55.5, 54.1, 41.3, 35.2,26.4; IR (cm⁻¹): 1655, 1506, 1483, 1431, 1350, 1302, 1248, 1221, 1176,1119, 864, 843, 804, 741, 700; LC/MS (M+H=603).

Example 42

Cyclopropane-1,1-dicarboxylic acid[4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide. To a flask containingcyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide(4-fluoro-phenyl)-amide (2.25 g, 6.7 mmol) and trifluoromethanesulfonicacid 7-benzyloxy-6-methoxy-quinolin-4-yl ester (1.87 g, 4.5 mmol) wasadded dry 2,6-lutidine (9 mL). The reaction mixture was heated to reflux(143° C.) with vigorous stirring. The reaction progress was monitored byLC-MS. 2,6-Lutidine was removed under reduced pressure when the reactionwas complete (about 6 h). The residue was treated with charcoal (1.5 g)in refluxing EtOAc (50 mL) for 15 min, and filtered through celite. Thevolume of the filtrate was reduced to about 20 mL and was added 20 mL of1 N HCl. The crude product precipitated as the HCl salt, which wasfiltered and washed with EtOAc and H₂O (88% purity by analytical HPLC).The HCl salt was free-based with saturated aqueous NaHCO₃ solution.Further purification by column chromatography (hexans:EtOAc=1:4) gavecyclopropane-1,1-dicarboxylic acid[4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide as an off-white solid (1.3 g, 48% yield. ¹H NMR(400 MHz, DMSO, d₆): 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1H), 7.92(dd, 1H), 7.65 (m, 2H), 7.54 (m, 5H), 7.41 (m, 4H), 7.17 (m, 2H), 6.43(d, 1H), 5.32 (s, 2H), 3.97 (s, 3H), 1.48 (m, 4H). LC/MS Calcd for[M+H]⁺ 596.2, found 596.3.

Example 43

Cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide. To a solution of thecyclopropane-1,1-dicarboxylic acid[4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide (22.4 g, 37.6 mmol) in EtOH (340 mL) was added1,4-cyclohexadiene (35 mL, 376 mmol) and 10% Pd/C (2.08 g). The reactionmixture was then heated at 65° C. with stirring for 3 h (Caution: H₂ gasis released from the reaction). It was then allowed to cool to roomtemperature, and filtered through celite followed by a MeOH wash. Thesolution was then concentrated under reduced pressure. The yellowresidue was taken into EtOAc (1 L). The EtOAc solution was washed withwater (1×), brine (2×), dried over MgSO₄ and concentrated in vacuo.Cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide was obtained as a yellow solid (17.3 g, 91.1%yield), which were carried on to the next reaction without furtherpurification. ¹H NMR (400 MHz, DMSO, d6): 10.39 (s, 1H), 10.15 (s, 1H),10.00 (s, 1H), 8.38 (d, 1H), 7.88 (dd, 1H), 7.63 (m, 2H), 7.50 (m, 2H),7.40 (t, 1H), 7.27 (s, 1H), 7.14 (m, 2H), 6.33 (d, 1H), 3.95 (s, 3H),1.47 (m, 4H). LC/MS Calcd for [M+H]⁺ 506.2, found 506.3. Anal. HPLC:99.4% pure.

Example 44

N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.To a mechanically stirred slurry of cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (16.6 g, 32.8 mmol) and potassium carbonate(13.6 g, 98.6 mmol) in DMF (250 mL) was added4-(3-chloropropyl)-morpholine hydrochloride (13, 7.92 g, 39.6 mmol). Theresulting mixture was heated at 90° C. for 5 hours (until phenolcompletely consumed). The reaction mixture was allowed to cool to roomtemperature, then dumped into water (900 mL), followed by extractionwith EtOAc (3×). The combined extracts were washed with 5% LiCl (aq.)(3×) and brine (1×) followed by drying over MgSO₄ and concentration invacuo. The crude (1 8.8 g) obtained as brown solid was further purifiedby flash chromatography [silica gel, 4-stage gradient system: 1) EtOAc;2) EtOAc:MeOH:7N NH₃/MeOH (95:5:0.5); 3) DCM:MeOH:7N NH₃/MeOH(95:5:0.5); 4) DCM:MeOH: 7N NH₃/MeOH (93:8:1)], affordingN-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidewas obtained as an off white solid (15.0 g, 72% yield). ¹H NMR (400 MHz,DMSO-d₆): 10.41 (s, 1H), 10.02 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H),7.65 (m, 2H), 7.53 (m, 2H), 7.42 (t, 1H), 7.40 (s, 1H), 7.16 (m, 2H),6.42 (d, 1H), 4.20 (t, 2H), 3.96 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H),2.39 (br, s, 4H), 1.98 (m, 2H), 1.48 (m, 4H). LC/MS Calcd for [M+H]+633.3, found 633.0.

Example 45

Cyclopropane-1,1-dicarboxylic acid[4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide: A mixture of7-benzyloxy-4-chloro-6-methoxy-quinazoline (5 g, 16.67 mmol),cyclopropane-1,1-dicarboxylic acid (3-fluoro-4-hydroxy-phenyl)-amide(4-fluoro-phenyl)-amide (8.3 g, 25 mmol), potassium carbonate (125 mmol,17.25 g), and dimethylacetamide (125 ml) was heated 50° C. with stirringfor 16 h. Reaction mixture was poured onto ice/water (600 ml) andstirred for 30 minutes, and filtered. The solid was dissolved in ethylacetate and washed with water (1×), brine, and concentrated. The crudewas purified on silica get column eluting with 30% acetone in hexanes toyield cyclopropane-1,1-dicarboxylic acid[4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide (7.5 g, 76%). ¹H NMR (CDCl₃): 8.64 (1H, br. s),8.55 (1H, s), 8.33 (1H, br. s), 7.74-7.71 (1H, dd), 7.54 (1H, s),7.48-7.33 (8H, m), 7.31-7.24 (2H, m), 7.06-7.02 (2H, m), 5.32 (2H, s),4.06 (3H, s), 1.77-1.74 (2H, m), 1.63-1.61 (2H, m).

Example 46

Cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide. To a mixture of cyclopropane-1,1-dicarboxylicacid[4-(7-benzyloxy-6-methoxy-quinazolin-4-yloxy)-3-fluoro-phenyl]-amide(4-fluoro-phenyl)-amide (7.5 g, 12.6 mmol), acetic acid (few drops),dichloromethane (50 ml) and methanol (100 ml) was added 10% Pd/C (700mg). The mixture was agitated in hydrogen gas (40 psi) until thereaction was complete (ca. 4 hr). The solution was filtered throughcelite and concentrated to give a crude product as a solid. The crudeproduct was triturated with ether, and filtered. The filter cake wasdried in vacuo to yield cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (6.1 g, 95% yield). ¹H NMR (dmso-d6): 10.86 (1H,br. s), 10.34 (1H, br. s), 10.04 (1H, br. s), 8.46 (1H, s), 7.84-7.80(1H, dd), 7.66-7.62 (2H, m), 7.55 (1H, s), 7.47-7.45 (1H, m), 7.41-7.37(1H, m), 7.24 (1H, s), 7.18-7.13 (2H, t), 3.98 (3H, s), 1.46 (4H, s).

Example 47

N-[3-Fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.To a mixture of cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (1.5 g, 2.96 mmol),4-(3-hydroxypropyl)morpholine (0.623 mL, 4.5 mmol), triphenylphosphine(1.18 g, 4.5 mmol), and dichloromethane (50 mL) was added diisopropylazodicarboxylate (0.886 mL, 4.5 mmol). The mixture was stirred at roomtemperature for 16 h, monitored by LCMS. After removal of solvent, thecrude mixture was separated by flash column chromatography (silica),eluting with 5% methanol in dichloromethane to giveN-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(890 mg, 47% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 10.36 (br s, 1H),10.05 (br s, 1H), 8.55 (s, 1H), 7.83 (m, 1H), 7.64 (m, 2H), 7.57 (s,1H), 7.44 (m, 3H), 7.18 (t, 2H), 4.27 (m, 2H), 3.99 (s, 3H), 3.61 (m,6H), 2.40 (m, 4H), 2.01 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]⁺634.2, found 634.3.

Example 48

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.To a solution of cyclopropane-1,1-dicarboxylic acid(4-fluoro-phenyl)-amide (4-hydroxy-phenyl)-amide (6.98 g, 22.2 mmol) inanhydrous 2,6-lutidine (50 mL) was added trifluoromethanesulfonic acid6,7-dimethoxy-quinolin-4-yl ester (5 g, 14.8 mmol). The reaction mixturewas heated at 165° C. in a sealed pressure tube with stirring for 18 h.The reaction mixture was concentrated on high vacuum to completelyremove lutidine. The resulting solid material was dissolved in DCM (250mL), and washed several times with 1 N sodium hydroxide to remove theexcess phenol. The crude mixture was loaded on a silica gel flash columnand eluted with 75% EtOAc-hexanes, affordingN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(3.2 g, 44%). ¹H NMR (400 MHz, d₆-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H),8.4 (s, 1H), 7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25(m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS:M+H=502.

Example 49

4,7-Dichloroquinoline. Phosphorus oxychloride (4 mL, 429 mmol) was addedto 7-chloro-4-hydroxyquinoline 2.86 g, 15.9 mmol) in a round bottomflask equipped with a reflux condenser. The mixture was heated to refluxfor 2 h, then allowed to cool to room temperature. The solution wasconcentrated in vacuo to a thick oil, then dumped over cracked ice. Theresulting solution was neutralized with saturated NaHCO₃ (aq). Theslurry was filtered and washed with water. The solids were dried undervacuum, afforded 4,7-dichloroquinoline as a white solid (2.79 g, 88.5%yield).

Example 50

4-[4-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester. Cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (325 mg, 0.64 mmol),4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester(193 mg, 0.66 mmol), K₂CO₃ (181 mg, 1.31 mmol) were combined in DMF (5ml) and heated to 80° C. overnight. The reaction was not complete andmore 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butylester (90 mg, 0.31 mmol) and K₂CO₃ (90 mg, 0.65 mmol) were added andheating at 80° C. continued for another night. The reaction mixture wasallowed to cool to room temperature, then diluted with EtOAc and washedwith H₂O (3×), sat'd NaCl (1×), dried (Na₂SO₄) and concentrated invacuo. The resulting crude material was purified by flash chromatography(1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give4-[4-(2-fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (273 mg, 60%). LC/MS Calcd for [M+H]⁺ 704.3, found704.4.

Example 51

Cyclopropane-1,1-dicarboxylic acid{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide, TFA salt.4-[4-(2-Fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (273 mg, 0.39 mmol) was dissolved in CH₂Cl₂ (8 ml)to which was added TFA (8 ml) and the mixture stirred at roomtemperature for 1 hr. The reaction mixture was concentrated in vacuo andthe resulting oil triturated with Et₂O. The resulting solids werefiltered, washed with Et₂O and dried under high vacuum to givecyclopropane-1,1-dicarboxylic acid{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide, TFA salt (222 mg, 80%). LC/MS Calcd for [M+H]⁺604.2, found 604.3.

Example 52

N-{3-Fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.Cyclopropane-1,1-dicarboxylic acid{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide, TFA salt (222 mg, 0.31 mmol), H₂O (3 ml), 37%formaldehyde in H₂O (0.18 ml) and acetic acid (27 drops) were combinedin acetonitrile (9 ml) to which was slowly added triacetoxyborohydride(561 mg, 2.65 mmol). The mixture was stirred at room temperature for 1-2hr, then diluted with 1N NaOH and H₂O and extracted with CH₂Cl₂ (3×).The combined CH₂Cl₂ extractions were washed with sat'd NaCl (1×), dried(Na₂SO₄) and concentrated in vacuo. The resulting residue was dissolvedin a minimum of 1:1 dioxane:EtOAc to which was added 4M HCl in dioxane(1-2 ml). The resulting solids were filtered, washed with EtOAc anddried under high vacuum to giveN-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,HCl salt (167 mg, 83%). 1HNMR (400 MHz, DMSO-d₆): δ 10.40 (s, 1H), 10.17(br s, 1H) 10.07 (s, 1H), 8.61 (s, 1H), 7.85 (m, 1H), 7.65 (m, 2H), 7.48(m, 2H), 7.42 (t, 1H), 7.16 (t, 2H), 4.12 (2, 2H), 4.00 (s, 3H), 3.46(m, 2H), 2.99 (m, 2H), 2.73 (d, 3H), 2.13 (m, 1H), 2.01 (m, 2H), 1.63(m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]⁺ 618.2, found 618.3.

Synthesis of Bridged Bicyclics

The following describes synthesis of bridged bicyclics with appendedleaving groups for use as, for example, alkylating agents. In thecontext of this invention, these alkylating agents are used, forexample, to alkylate the quinazoline or quinolines on the 6- or7-oxygens to make compounds of the invention. The invention is notlimited to alkylation chemistry to append such bridged bicyclics, butrather the aforementioned description is meant only to be illustrativeof an aspect of the invention.

Example 53

1,4:3,6-dianhydro-2-O-methyl-5-O-(methylsulfonyl)-D-glucitol: To asolution of 1,4:3,6-dianhydro-2-O-methyl-D-glucitol (1.19 g, 7.4 mmol)in dichloromethane was added pyridine (1 mL, 12.36 mmol) followed bymethanesulfonyl chloride (0.69 mL, 8.92 mmol) and the mixture wasallowed to stir at room temperature over 12 hours. The solvent wasremoved and the amorphous residue was partitioned with ethyl acetate and0.1M aqueous hydrochloric acid. The aqueous phase was extracted oncewith additional ethyl acetate and the combined organic layers werewashed with saturated aqueous sodium chloride then dried over anhydrousmagnesium sulfate. Filtration and concentration followed by drying invacuo afforded1,4:3,6-dianhydro-2-O-methyl-5-O-(methylsulfonyl)-D-glucitol (1.67 g,94% yield) as a colorless oil. GC/MS calculated for C₈H₁₄SO₆: 238 (M⁺).

Example 54

1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructose ethylene glycolacetal: A solution of 1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructose(2.00 g, 8.06 mmol), ethylene glycol (5.00 g, 80.6 mmol), andp-toluenesulfonic acid (1.53 g, 8.06 mmol) in benzene (100 mL) wasrefluxed for 90 min using a Dean-Stark Trap apparatus. The reactionmixture was diluted with ethyl acetate (100 mL), washed with saturatedaqueous sodium bicarbonate (2×50 mL) then brine (50 mL), and dried overanhydrous sodium sulfate. Filtration, concentration and columnchromatography on silica (1:1 hexane/ethyl acetate) provided 1.44 g (61%yield) of 1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructose ethyleneglycol acetal as a colorless solid. ¹H NMR (400 MHz; CDCl₃): 8.08 (m,2H), 7.58 (m, 1H), 7.54 (m, 2H), 5.38 (dd, 1H), 4.97 (t, 1H), 4.21-4.02(m, 7H), 3.86 (d, 1H), 3.75 (d, 1H).

Example 55

1,4:3,6-dianhydro-D-fructose ethylene glycol acetal: To a solution of1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-D-fructose ethylene glycol acetal(1.44 g, 4.93 mmol) in methanol (40 mL) was added 50% aqueous sodiumhydroxide (0.38 g, 4.75 mmol) and the mixture was stirred at roomtemperature for 30 minutes. Neutralization with 1M HCl, followed byconcentration and column chromatography on silica (1:2 hexane/ethylacetate) provided 0.74 g (80% yield) of 1,4:3,6-dianhydro-D-fructoseethylene glycol acetal as a colorless solid. ¹H NMR (400 MHz; CDCl₃):4.60 (t, 1H), 4.32 (m, 1H), 4.14 (d, 1H), 4.05-3.98 (m, 5H), 3.82 (s,2H), 3.62 (dd, 1H), 2.65 (d, 1H).

1,4:3,6-dianhydro-5-O-(methylsulfonyl)-D-fructose ethylene glycolacetal: To a solution of 1,4:3,6-dianhydro-D-fructose ethylene glycolacetal (0.74 g, 3.93 mmol) and triethylamine (1.20 g, 11.86 mmol) indichloromethane (40 mL) was added methanesulfonyl chloride (0.90 g, 7.88mmol) at 0° C. under nitrogen. The solution was warmed to roomtemperature and stirred for 13 h. Dichloromethane (50 mL) was added, andthe organic layer was washed with saturated aqueous sodium bicarbonate(30 mL), water (30 mL), and brine (30 mL) then dried over anhydroussodium sulfate. Filtration and concentration provided 1.02 g (97%) of1,4:3,6-dianhydro-5-O-(methylsulfonyl)-D-fructose ethylene glycol acetalas a yellow oil. ¹H NMR (400 MHz; CDCl₃): 5.08 (m, 1H), 4.82 (t, 1H),4.13 (dd, 1H), 4.04 (m, 4H), 3.93 (dd, 1H), 3.87 (d, 1H), 3.81 (d, 1H),3.13 (s, 3H).

Example 56

1,4:3,6-dianhydro-2-deoxy-2-methylidene-D-arabino-hexitol: To a solutionof 1,4:3,6-dianhydro-2-deoxy-2-methylidene-5-O-(phenylcarbonyl)-D-arabino-hexitol(329 mg, 1.34 mmol) in methanol (10 mL) was added 50% aqueous sodiumhydroxide (95 mg, 1.19 mmol) and the mixture was stirred at roomtemperature for 30 minutes. Neutralization with 4M hydrogen chloride in1,4-dioxane followed by concentration and column chromatography onsilica (1:1 hexane/ethyl acetate) provided 141 mg (74%) of1,4:3,6-dianhydro-2-deoxy-2-methylidene-D-arabino-hexitol as a colorlesssolid. ¹H NMR (400 MHz; CDCl₃): 5.37 (m, 1H), 5.20 (m, 1H), 4.80 (m,1H), 4.54 (m, 2H), 4.43 (m, 1H), 4.26 (m, 1H), 3.95 (dd, 1H), 3.54 (dd,1H), 2.70 (d, 1H).

1,4:3,6-dianhydro-2-deoxy-2-methylidene-5-O-(methylsulfonyl)-D-arabino-hexitol:To a solution of1,4:3,6-dianhydro-2-deoxy-2-methylidene-D-arabino-hexitol (135 mg, 0.95mmol) and triethylamine (288 mg, 2.85 mmol) in dichloromethane (10 mL)was added methanesulfonyl chloride (222 mg, 1.94 mmol) at 0° C. undernitrogen. The solution was warmed to room temperature and stirred for 18h. Dichloromethane (50 mL) was added and the organic layer was washedwith saturated aqueous sodium bicarbonate (2×25 mL), water (25 mL) andbrine (25 mL) then dried over anhydrous sodium sulfate. Filtration andconcentration provided 213 mg (72%) of1,4:3,6-dianhydro-2-deoxy-2-methylidene-5-O-(methylsulfonyl)-D-arabino-hexitolas a yellow oil. ¹H NMR (400 MHz; CDCl₃): 5.40 (m, 1H), 5.23 (m, 1H),5.04 (m, 1H), 4.85 (m, 1H), 4.73 (t, 1H), 4.58 (m, 1H), 4.41 (m, 1H),4.08 (dd, 1H), 3.86 (dd, 1H), 3.14 (s, 3H).

Example 57

1,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-L-arabino-hex-1-enitol:To a mixture of 1,4:3,6-dianhydro-5-O-(phenylcarbonyl)-(D)-glycitol(4.32 g, 17.3 mmol), triethylamine (4.91 mL, 35.3 mmol) and4-dimethylaminopyridine (0.63 g, 5.2 mmol) in dichloromethane (50 mL) at−10° to −15° was added trifluoromethanesulfonic anhydride (3.48 mL, 20.7mmol) dropwise over ten minutes and the resulting mixture was stirred atthis temperature for 3 hours. The mixture was poured into 100 mL ofice-water and extracted with dichloromethane (3×50 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered then concentrated. The crude triflate was suspended intoluene (50 mL) followed by addition of1,8-diazabicyclo[4,5,0]undec-7-ene (5.25 mL, 34.6 mmol) and the mixturewas stirred at room temperature for 18 hours. The reaction mixture waspoured into ice-water and partitioned then the aqueous portion wasextracted with dichloromethane (3×50 mL). The combined organic portionwas washed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flashed chromatography (silicagel, 5-20% ethyl acetate-hexane) to give1,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-L-arabino-hex-1-enitol,as a white solid, 3.10 g, 77% yield. ¹H NMR (400 MHz; CDCl₃): 8.08-8.06(m, 2H), 7.61-7.57 (m, 1H), 7.56-7.43 (m, 2H), 6.62-6.61 (d, 1H),5.48-5.46 (m, 1H), 5.32-5.26 (m, 1H), 5.13-5.10 (m, 2H), 4.18-4.14 (tr,1H), 3.61-3.56 (tr, 1H).

Example 58

Methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-L-glucofuranoside: To asolution of1,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-L-arabino-hex-1-enitol(1.00 g, 4.3 mmol) in methanol (17 mL) at −4° C. was added3-chloroperoxybenzoic acid (85%, 1.35 g, 8.6 mmol), and the resultingmixture was slowly warmed to room temperature and stirred for 18 hours.The reaction mixture was concentrated, diluted with dichloromethane (50mL), washed with saturated aqueous sodium bicarbonate solution, driedover sodium sulfate, filtered and concentrated. The residue was purifiedby flash chromatography (silica gel, 25-60% ethyl acetate-hexane) togive methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-L-glucofuranoside as awhite solid, 1.03 g, 83% yield. ¹H NMR (400 MHz; CDCl₃): 8.11-8.08 (d,2H), 7.61-7.56 (tr, 1H), 7.48-7.44 (m, 2H), 5.24-5.17 (m, 2H), 4.96 (s,1H), 4.57-4.56 (d, 1H), 4.27 (s, 1H), 4.22-4.18 (dd, 1H), 4.08-4.04 (dd,1H) 3.36 (s, 3H).

Methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-1-L-glucofuranoside:A mixture of methyl 3,6-anhydro-5-O-(phenylcarbonyl)-β-L-glucofuranoside(1.03 g, 3.7 mmol), silver (I) oxide (0.85 g, 3.7 mmol) and methyliodide (0.34 mL, 5.5 mmol) in DMF (2 mL) was heated at 60° C. for 1hour. After cooling to room temperature the reaction mixture was dilutedwith ethyl acetate (50 mL), filtered over celite, adsorbed on silica gel(10 g) and purified by flash chromatography (silica gel, 5-30% ethylacetate-hexane) to give methyl3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside as acolorless oil, 0.82 g, 76% yield. ¹H NMR (400 MHz; CDCl₃): 8.11-8.09 (d,2H), 7.60-7.56 (m, 1H), 7.46-7.44 (m, 2H), 5.24-5.20 (m, 1H), 5.18-5.09(tr, 1H), 4.99 (s, 1H), 4.61-4.60 (d, 1H), 4.21-4.17 (tr, 1H), 4.08-4.03(tr, 1H), 3.81 (s, 1H), 3.40 (s, 3H), 3.57 (s, 3H).

Methyl 3,6-anhydro-2-O-methyl-α-D-idofuranoside: A solution of methyl3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside (820 mg,3.1 mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (10mL) was stirred at room temperature for 30 minutes. The material wasadsorbed on silica gel (5 g) and passed through a short column (15%ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl3,6-anhydro-2-O-methyl-α-D-idofuranoside as a colorless oil, 420 mg, 85%yield. ¹H NMR (400 MHz; CDCl₃): 5.04 (s, 1H), 5.84-5.81 (tr, 1H),4.44-4.42 (tr, 1H), 4.25-4.19 (m, 1H), 3.85-3.75 (m, 1H), 3.49 (s, 3H),3.43 (s, 3H), 2.75-2.72 (d, 1H).

Methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-L-glucofuranoside:Methyl 3,6-anhydro-2-O-methyl-α-D-idofuranoside (420 mg, 2.6 mmol) wasdissolved in dichloromethane (10 mL) and pyridine (0.36 mL, 3.7 mmol) at0° C. Methanesulfonyl chloride (0.14 mL, 3.1 mmol) was added and theresulting mixture was stirred at 0° C. for 1 hour then at roomtemperature for 2 hours. The reaction mixture was washed with water andsaturated aqueous sodium bicarbonate solution, dried over anhydroussodium sulfate, filtered and concentrated to give methyl3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-β-L-glucofuranoside as acolorless oil, 669 mg, 95% yield, which was used without furtherpurification.

Example 59

3,6-anhydro-5-O-(phenylcarbonyl)-α-L-glucofuranose: A mixture of osmiumtetroxide (4% in water, 0.25 mL, 0.03 mmol) and N-methylmorpholine (505mg, 4.3 mmol) in 3 mL of 50% acetone in water was warmed to 60° C. Asolution of1,4:3,6-dianhydro-2-deoxy-5-O-(phenylcarbonyl)-L-arabino-hex-1-enitol(2.00 g, 8.6 mmol) in 6 mL of 50% acetone in water was added over 3hours. During this time an additional amount of N-methylmorpholine (1.01g, 8.6 mmol) was added in small portions periodically. Upon completionof the addition process the reaction was stirred for another hour andcooled to room temperature. The crude mixture was applied to a column ofsilica gel and flashed (0-6% methanol in 1:1 ethyl acetate:hexane) togive 3,6-anhydro-5-O-(phenylcarbonyl)-α-L-glucofuranose as a whitesolid, 1.5 g, 65% yield. ¹H NMR (400 MHz; DMSO-d₆): 8.01-7.95, (m, 2H),7.68-7.66 (m, 1H), 7.57-7.53 (m, 2H), 5.18-5.11 (m, 2H), 4.85-4.81 (m,1H, m), 4.37-4.35 (m, 1H), 4.05-3.96 (m, 2H), 3.85-3.83 (m, 1H).

3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-α-L-glucofuranoside:3,6-Anhydro-5-O-(phenylcarbonyl)-α-L-glucofuranose (576 mg, 2.2 mmol)was added to a mixture of sodium hydride (60% oil dispersion, 346 mg,8.7 mmol) and methyl iodide (0.54 mL, 8.7 mmol) in 5 mL of DMF at 0° C.and the resulting mixture was stirred for 1 hour. The reaction mixturewas diluted with ethyl acetate and quenched with water (5 mL). Theaqueous portion was extracted with ethyl acetate (3×5 mL). The combinedorganic portion was washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified by flashedchromatography (silica gel, 5-20% ethyl acetate in hexane) to give3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-α-L-glucofuranoside as awhite solid, 270 mg, 42% yield. ¹H NMR (400 MHz; CDCl₃): 8.09-8.07 (m,2H), 7.61-7.57 (m, 1H), 7.48-7.27 (m, 2H), 5.25-5.22 (m, 1H), 5.07-5.06(d, 1H), 4.94-4.91 (m, 1H), 4.73-4.71 (m, 1H), 4.20-4.16 (m, 1H),3.96-3.94 (m, 1H), 3.85-3.83 (tr, 1H), 3.50 (s, 3H), 3.42 (s, 3H).

Methyl 3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-α-L-glucofuranoside:A solution of methyl3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-α-L-glucofuranoside (230 mg,0.92 mmol) and 50% sodium hydroxide (74 mg, 0.92 mmol) in methanol (5mL) was stirred at room temperature for 30 minutes. The mixture wasadsorbed on silica gel (2 g) and passed through a short column (15%ethyl acetate in hexanes to 5% methanol in ethyl acetate) to afford acolorless oil which was employed directly in the next step, 140 mg, 0.72mmol, 95% yield. The alcohol was dissolved in dichloromethane (5 mL) andpyridine (121 μL, 1.03 mmol) was added at 0° C. Methanesulfonyl chloride(27 μL, 0.88 mmol) was added and the resulting mixture was stirred at 0°C. for 1 hour then at room temperature for 2 hours. The reaction mixturewas washed with water and saturated aqueous sodium bicarbonate solution,dried over sodium sulfate, filtered and concentrated to give methyl3,6-anhydro-2-O-methyl-5-O-(methylsulfonyl)-α-L-glucofuranoside as acolorless oil, 190 mg, 96% yield.

Example 60

36-Anhydro-1,2-O-(1-methylethylidene)-5-O-(phenylcarbonyl)-α-L-glucofuranose:A mixture of 3,6-anhydro-5-O-(phenylcarbonyl)-α-L-glucofuranose (1.00g), 2,2-dimethoxy propane (0.63 mL), p-toluenesulfonic acid (20 mg) andbenzene (10 mL) was heated at reflux for 3 hours. The reaction mixturewas cooled then adsorbed on silica gel (10 g) and purified by flashchromatography (silica gel, 5-35% ethyl acetate in hexanes) to give3,6-anhydro-1,2-O-(1-methylethylidene)-5-O-(phenylcarbonyl)-α-L-glucofuranoseas colorless oil, 0.85 g, 74% yield. ¹H NMR (400 MHz; CDCl₃): 8.08-8.06(d, 2H), 7.59-7.56 (tr, 1H), 7.46-7.42 (m, 2H), 5.99-5.98 (d, 1H),5.35-5.31 (tr, 1H), 5.10-5.08 (d, 1H), 4.66-4.65 (d, 1H), 4.61-4.60 (d,1H), 4.20-4.16 (dd, 1H), 3.91-3.74 (tr, 1H,), 1.50 (s, 3H), 1.34 (s,3H).

3,6-Anhydro-1,2-O-(1-methylethylidene)-5-O-(methylsulfonyl)-α-L-glucofuranose:A solution of3,6-anhydro-1,2-O-(1-methylethylidene)-5-O-(phenylcarbonyl)-α-L-glucofuranose(850 mg) and 50% sodium hydroxide (111 mg) in methanol (10 mL) wasstirred at room temperature for 30 minutes. The mixture was thenadsorbed on silica gel (5 g) and passed through a short column (15%ethyl acetate in hexanes to 5% methanol in ethyl acetate) and thealcohol intermediate, 390 mg, 70% yield, was used immediately in thenext step. The alcohol was dissolved in dichloromethane (10 mL) andpyridine (0.32 mL) at 0° C. Methanesulfonyl chloride (0.12 mL) was addedand the resulting mixture was stirred at 0° C. for 1 hour then at roomtemperature for 2 hours. The reaction mixture was washed with water andsaturated aqueous sodium bicarbonate solution, dried over anhydroussodium sulfate, filtered and concentrated to give3,6-anhydro-1,2-O-(1-methylethylidene)-5-O-(methylsulfonyl)-α-L-glucofuranoseas a colorless oil, 485 mg, 90% yield, which was immediately employed inthe next step.

Example 61

(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine:(S)-(+)-Prolinol (6.00 g, 59.3 mmol) was added to epichlorohydrin (47mL, 600 mmol) at 0° C. The solution was stirred at 40° C. for 0.5 h andthen concentrated in vacuo. The residual oil was cooled in an ice bathand concentrated sulfuric acid (18 mL) was added dropwise with stirring.The mixture was heated at 170-180° C. for 1.5 h, poured into ice (300mL) and then basified with sodium carbonate to pH˜8. The mixture waspartitioned with ethyl acetate/hexanes and filtered. The filtrate wasseparated and the aqueous portion was extracted twice with ethylacetate. The combined organic portion was dried over sodium sulfate,filtered and concentrated in vacuo to afford oil that was purified bycolumn chromatography (ethyl acetate for less polar product and then 30%methanol in ethyl acetate).(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (lesspolar product) (1.87 g, 10.7 mmol, 18% yield): ¹H NMR (400 MHz, CDCl₃):4.06 (dd, 1H), 3.79-3.71 (m, 1H), 3.60-3.48 (m, 2H), 3.36 (dd, 1H), 3.15(dd, 1H), 3.13-3.06 (m, 1H), 2.21-2.01 (m, 3H), 1.90-1.68 (m, 3H),1.39-1.24 (m, 1H); MS (EI) for C₈H₁₄NOCl: 176 (MH⁺).(3R,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (1.54g, 8.77 mmol, 15% yield): ¹H NMR (400 MHz, CDCl₃): 3.94-3.77 (m, 4H),3.55 (dd, 1H), 3.02-2.93 (m, 2H), 2.45 (dd, 1H), 2.29-2.15 (m, 2H),1.88-1.64 (m, 3H), 1.49-1.38 (m, 1H); MS (EI) for C₈H₁₄NOCl: 176 (MH⁺).

Using the same or analogous synthetic techniques and/or substitutingwith alternative starting materials, the following were prepared:

(3R,8aR)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine: ¹H NMR(400 MHz, CDCl₃): 4.05 (dd, 1H), 3.79-3.70 (m, 1H), 3.61-3.48 (m, 2H),3.35 (dd, 1H), 3.15 (dd, 1H), 3.13-3.07 (m, 1H), 2.21-2.01 (m, 3H),1.89-1.67 (m, 3H), 1.39-1.25 (m, 1H); MS (EI) for C₈H₁₄NOCl: 176 (MH⁺).

(3S,8aR)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine: ¹H NMR(400 MHz, CDCl₃): 3.93-3.77 (m, 4H), 3.55 (dd, 1H), 3.02-2.93 (m, 2H),2.45 (dd, 1H), 2.30-2.15 (m, 2H), 1.88-1.64 (m, 3H), 1.49-1.37 (m, 1H);MS (EI) for C₈H₁₄NOCl: 176 (MH⁺).

Example 62

(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate:(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (2.30g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred indimethylformamide (25 mL) at 140° C. for 20 h. The mixture waspartitioned between ethyl acetate and water. The organic portion waswashed twice with water, then with brine, dried over sodium sulfate,filtered and concentrated in vacuo to afford(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate as abrown oil (2.53 g, 12.7 mmol, 97% yield). ¹H NMR (400 MHz, CDCl₃):4.14-4.02 (m, 3H), 3.81-3.72 (m, 1H), 3.37-3.31 (m, 1H), 3.09 (dt, 1H),3.00 (dd, 1H), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H),1.39-1.24 (m, 1H); MS (EI) for C₀₀H₁₇NO₃: 200 (MH⁺).

(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][41]oxazin-3-ylmethanol:(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate (2.36g, 11.9 mmol) was treated with sodium methoxide (25 wt % solution inmethanol; 2.7 mL) for 0.5 h. The mixture was cooled in an ice bath and asolution of 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) was added slowly.The mixture was stirred at room temperature for 5 minutes and then wasconcentrated in vacuo to afford a suspension which was diluted withdichloromethane, filtered and the filtrate was concentrated in vacuo toafford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol as abrown oil (1.93 g, >100% yield). ¹H NMR (400 MHz, CDCl₃): 4.05 (dd, 1H),3.73-3.65 (m, 2H), 3.62-3.56 (m, 1H), 3.39-3.34 (m, 1H), 3.10 (dt, 1H),3.00-2.95 (m, 1H), 2.24-1.98 (m, 4H), 1.97-1.70 (m, 3H), 1.44-1.28 (m,1H); MS (EI) for C₈H₁₅NO₂: 158 (MH⁺).

(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethylmethanesulfonate:(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol (1.00 g,6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamine(2.4 mL, 17.3 mmol) was added at 0° C. followed by dropwise addition ofmethanesulfonyl chloride (0.93 mL, 12.0 mmol). The solution was warmedto room temperature and stirred for 1.25 h and then was concentrated invacuo. The residue was partitioned between ethyl acetate and saturatedsodium bicarbonate solution. The organic portion was washed withsaturated sodium bicarbonate solution. The combined aqueous portion wasextracted with ethyl acetate. The combined organic portion was washedwith brine, dried over sodium sulfate, filtered and concentrated invacuo to afford(3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethylmethanesulfonate as an orange-brown oil (1.20 g, 5.1 mmol, 80% yield).MS (EI) for C₉H₁₇NO₄S: 236 (MH⁺).

Example 63

Octahydro-2H-quinolizin-3-ylmethanol: Ethyloctahydro-2H-quinolizine-3-carboxylate (2.35 g, 11.1 mmol) was addeddropwise to a stirred suspension of lithium aluminum hydride (1 Msolution in tetrahydrofuran, 33 mL, 33 mmol) in tetrahydrofuran (50 mL)at 0° C. The reaction was stirred at room temperature for 3 h. Themixture was cooled in an ice bath and ethyl acetate (6 mL) was addedslowly, followed by water (1.25 mL), 15% aqueous sodium hydroxidesolution (5 mL) and water (1.25 mL). The mixture was filtered through apad of celite and washed with ether. The filtrate was concentrated invacuo and dried rigorously to affordoctahydro-2H-quinolizin-3-ylmethanol as a yellow oil (1.66 g, 9.82 mmol,88% yield). MS (EI) for C₁₀H₁₉NO: 170 (MH⁺).

Octahydro-2H-quinolizin-3-ylmethyl methanesulfonate:Octahydro-2H-quinolizin-3-ylmethanol (600 mg, 3.55 mmol) was dissolvedin dichloromethane (8 mL) and triethylamine (1.5 mL, 10.8 mmol) wasadded at 0° C. followed by dropwise addition of methanesulfonyl chloride(0.56 mL, 7.16 mmol). The solution was warmed to room temperature andstirred for 1.25 h and then was concentrated in vacuo. The residue waspartitioned between ethyl acetate and saturated sodium bicarbonatesolution. The aqueous portion was extracted with ethyl acetate. Thecombined organic portion was washed with brine, dried over sodiumsulfate, filtered and concentrated in vacuo to affordoctahydro-2H-quinolizin-3-ylmethyl methanesulfonate as an orange oil(796 mg, 3.22 mmol, 91% yield). MS (EI) for C₁₁H₂₁NO₃S: 248 (MH⁺).

Example 64

(3S,8aS)-3-(Hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one: Asolution of methyl1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(3.50 g, 10.4 mmol) in methanol was added to 5% palladium on carbon (50wt. % in water) in methanol and treated with hydrogen at 40 psi for 1 h.The mixture was filtered and the filtrate was brought to reflux brieflyand then cooled and concentrated in vacuo to afford(3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as acolorless solid (1.50 g, 8.83 mmol, 85% yield). ¹H NMR (400 MHz, CDCl₃):7.28-7.22 (m, 1H), 3.83-3.75 (m, 1H), 3.69 (dd, 1H), 3.56 (dd, 1H), 3.31(t, 1H), 3.08 (dd, 1H), 2.92 (dt, 1H), 2.76-2.70 (m, 1H), 2.66 (dd, 1H),2.28-2.16 (m, 1H), 2.02-1.73 (m, 3H); MS (EI) for C₈H₁₄N₂O₂: 171 (MH⁺).

(3S8aS)-3-({[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydro-pyrrolo[1,2-a]pyrazin-1(2H)-one:To a solution of (3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (1.49 g, 8.82 mmol) indimethylformamide (20 mL) was added triethylamine (2.45 mL, 17.6 mmol)and 4-dimethylaminopyridine (90 mg, 0.882 mmol). The solution was cooledin an ice bath and tert-butyldimethylsilyl chloride (2.66 g, 17.6 mmol)was added. The mixture was warmed to room temperature and stirred for 14h. The mixture was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and water. The aqueous portion was extracted twicewith ethyl acetate. The combined organic portion was dried over sodiumsulfate, filtered and concentrated in vacuo to afford a pale brown solidwhich was triturated with ethyl acetate to afford(3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as an off-white solid (1.74 g,5.84 mmol, 66% yield). ¹H NMR (400 MHz, CDCl₃): 6.09-5.90 (m, 1H),3.86-3.76 (m, 1H), 3.63 (dd, 1H), 3.44 (dd, 1H), 3.25 (t, 1H), 3.10(ddd, 1H), 2.98-2.90 (m, 1H), 2.68-2.60 (m, 1H), 2.52 (dd, 1H),2.28-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.93-1.74 (m, 2H), 0.90 (s, 9H),0.07 (s, 6H); MS (EI) for C₁₄H₂₈N₂O₂Si: 285 (MH⁺).

(3S,8aS)-3-({[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one:(3S,8aS)-3-({[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one(1.51 g, 5.32 mmol) in dimethylformamide (8 mL) was added to anice-cooled suspension of sodium hydride (60 wt. % dispersion in oil; 213mg, 5.32 mmol) in dimethylformamide (8 mL). The mixture was stirred at0° C. for 0.25 h and then iodomethane (0.332 mL, 5.32 mmol) was addeddropwise. The mixture was stirred at room temperature for 0.5 h and thenwas stirred at 70° C. for 2 h. The mixture was concentrated in vacuo andthe residue was partitioned between ethyl acetate and water. The aqueousportion was extracted with ethyl acetate. The combined organic portionwas dried over sodium sulfate, filtered and concentrated in vacuo toafford(3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-oneas a yellow oil (1.552 g, 5.21 mmol) which was dissolved intetrahydrofuran (20 mL) and treated with tetrabutylammonium fluoride(1.0M solution in tetrahydrofuran; 10.4 mL, 10.4 mmol) for 2 h at roomtemperature. The mixture was concentrated in vacuo and purified bycolumn chromatography (10% methanol in dichloromethane) to afford(3S,8aS)-3-(hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-oneas a yellow oil (496 mg, 2.70 mmol, 51% yield from(3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one).¹H NMR (400 MHz, CDCl₃): 3.98-3.93 (m, 1H), 3.86 (dd, 1H), 3.61-3.55 (m,1H), 3.29-3.25 (m, 1H), 3.09-3.03 (m, 1H), 3.03-2.97 (m, 1H), 3.02 (s,3H), 2.93 (dd, 1H), 2.87-2.79 (m, 1H), 2.32-2.21 (m, 1H), 2.00-1.86 (m,2H), 1.83-1.64 (m, 1H); MS (EI) for C₉H₁₆N₂O₂: 185 (MH⁺).

Example 65

1,2-Dideoxy-1-[(2S)-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy)carbonyl]amino]-D-glycero-hexitol: To a solution of2-deoxy-2-{[(phenylmethyloxy)carbonyl]amino}-D-glycero-hexopyranose (5.0g, 0.016 mol) in methanol (500 mL) was added L-proline methyl esterhydrochloride (2.8 g, 0.022 mol) and sodium cyanoborohydride (3.4 g,0.054 mol). The solution was heated to 64° C. for 14 h. After cooling toroom temperature, the reaction mixture was concentrated in vacuo toafford1,2-dideoxy-1-[(2S)-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy)carbonyl]amino]-D-glycero-hexitol(6.81 g, 100%) as a clear and colorless oil. MS (EI) for C₂₀H₃₁N₂O₈: 427(MH⁺).

Example 66

Methyl1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate:1,2-dideoxy-1-[(2S)-2-(methoxycarbonyl)-1-pyrrolidinyl]-2-[[(phenylmethoxy)carbonyl]amino]-D-glycero-hexitol(6.81 g, 0.016 mol) was taken into water (100 mL) and the resultingsolution was cooled to 0° C. Sodium periodiate (14.8 g, 0.069 mol)dissolved in water was added dropwise and the resulting mixture wasstirred at 0° C. for 2 h. The reaction mixture was partitioned withdichloromethane (3×100 mL), dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was taken up in methanol(200 mL) and the resulting solution was cooled to 0° C. Sodiumborohydride (1.98 g, 0.052 mol) was added and the reaction mixture wasstirred for 1 h at 0° C. The reaction mixture was concentrated in vacuoand partitioned with dichloromethane and saturated aqueous ammoniumchloride. The organic layer was dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The resulting crude product waspurified by column chromatography (5% methanol in dichloromethane) toyield methyl1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(4.9 g, 92%) as a white solid. MS (EI) for C₁₇H₂₅N₂O₅: 337 (MH⁺).

Methyl1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate:Methyl1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) followed bythe addition of 4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) andtriethylamine (0.125 mL, 0.891 mmol) and the resulting mixture wascooled to 0° C. Methanesulfonyl chloride (0.060 mL, 0.773 mmol) wasadded dropwise and the reaction mixture was stirred for 1 h at 0° C. Themixture was partitioned between dichloromethane and saturated aqueoussodium bicarbonate. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to afford methyl1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate(246 mg, 100%) as a clear and colorless oil. MS (EI) for C₁₈H₂₇N₂O₇S:415 (MH⁺).

Example 67

1,1-Dimethylethyl(3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate:Under a nitrogen atmosphere, borane tetrahydrofuran complex (1M in THF,42 mL, 41.9 mmol) was diluted with tetrahydrofuran (42 mL) and cooledwith an ice bath. Neat 2,3-dimethylbut-2-ene (5.0 mL, 41.9 mmol) wasadded in portions over 0.25 h and the solution was stirred at 0° C. for3 h. A solution of 1,1-dimethylethyl(3aR,6aS)-5-methylidenehexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(1.98 g, 8.88 mmol) in tetrahydrofuran (10 mL) was added slowly, and thesolution was warmed to room temperature and stirred 12 h. After coolingto 0° C., 10% aqueous sodium hydroxide (17 mL, 41.7 mmol) was addedslowly, followed by 30% aqueous hydrogen peroxide (13 mL, 128 mmol) andthe solution was warmed to room temperature. The solvent was removed invacuo and the solution was partitioned between water and diethyl ether.The layers were separated and the aqueous layer was further extracted(3×50 mL diethyl ether). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to provide2.04 (95%) of 1,1-dimethylethyl(3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,which was used without purification. ¹H NMR (400 MHz, CDCl₃): 8.50(broad s, 1H), 3.66-3.46 (m, 3H), 3.20-3.00 (m, 2H), 2.70-2.59 (m, 2H),2.37-2.18 (m, 1H), 2.04 (m, 1H), 1.84 (broad s, 1H), 1.70-1.55 (m, 1H),1.46 (s, 9H), 1.17 (m, 1H), 0.93 (m, 1H).

1,1-Dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate:Methanesulfonyl chloride (0.2 mL, 2.48 mmol), was added dropwise to asolution of 1,1-dimethylethyl (3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.40 g, 1.65 mmol) andtriethylamine (0.69 mL, 4.95 mmol) in 20 mL dichloromethane at 0° C. andthe reaction mixture was stirred for 1 h at room temperature. Thesolvent was evaporated, the resulting crude mixture was diluted with 100mL ethyl acetate and washed with water (30 mL), 1M aqueous sodiumhydroxide, brine, 1M aqueous hydrochloric acid and brine again. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The resulting 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatewas used without further purification. MS (EI) for C₁₄H₂₅NO₅S: 320(MH⁺), 264 (M-tBu).

Example 68

1,1-Dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate:Sodium borohydride (0.15 g, 4.00 mmol), was added to a solution of1,1-dimethylethyl(3aR,6aS)-5-oxo-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.45 g,2.00 mmol) in 10 mL methanol at 0° C. and the reaction mixture wasstirred for 1 h at this temperature. The solvent was evaporated, thecrude mixture was diluted with 100 mL ethyl acetate and washed withwater (30 mL), 1M aqueous hydrochloric acid and brine. The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated togive 1,1-dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.44 g, 98%). ¹H NMR (400 MHz, d₆-DMSO): 4.08 (m, 1H), 3.40 (m, 2H),3.30 (m, 2H), 2.50 (m, 2H), 1.98 (m, 2H), 1.40 (s, 9H), 1.30 (m, 2H). MS(EI) for C₁₂H₂₁NO₃: 228 (MH⁺).

1,1-Dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate:Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to asolution of 1,1-dimethylethyl(3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 mLdichloromethane at 0° C. and the reaction mixture was stirred for 1 h atroom temperature. The solvent was evaporated, the resulting crudemixture was diluted with 100 mL ethyl acetate and washed with water (30mL), brine, 1M aqueous hydrochloric acid and brine again. The organiclayer was dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting crude 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylatewas used without further purification. MS (EI) for C₁₃H₂₃NO₅S: 306(MH⁺).

Example 69

3-(Chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine: A solutionof (3R)-morpholin-3-ylmethanol (4.21 g, 36.0 mmol) in2-(chloromethyl)oxirane (28.2 mL, 0.360 mol) was heated to 40° C. for 3h and then the solution was concentrated in vacuo. The intermediate wascooled in an ice bath and treated with 30.0 mL of concentrated sulfuricacid. The mixture was heated to 170° C. for 2 h and then allowed to coolto room temperature. The mixture was poured into ice-water and solidsodium bicarbonate was carefully added until the solution was basic. 10%methanol in ethyl acetate was added and the biphasic mixture wasfiltered. The layers were separated and the aqueous layer was extracted(3×100 mL 10% methanol in ethyl acetate). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. Column chromatography (SiO₂, 2:5 hexanes:ethyl acetate) provided3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine 2.44 g(35%) as two separated diastereomers.(3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine:(0.886 g, 13% yield): ¹H NMR (400 MHz, CDCl₃): 3.91 (m, 3H), 3.82 (m,1H), 3.68 (dt, 1H), 3.61 (dd, 1H), 3.47 (dd, 1H), 3.35 (t, 1H), 3.19 (t,1H), 2.80 (d, 1H), 2.54 (m, 2H), 2.40 (m, 2H); MS (EI) for C₈H₁₄NO₂Cl:192 (MH⁺).(3S,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine:(1.55 g, 22% yield): ¹H NMR (400 MHz, CDCl₃): 3.85 (m, 2H), 3.73 (m,3H), 3.50 (m, 2H), 3.29 (t, 1H), 3.18 (t, 1H), 2.85 (dd, 1H), 2.64 (dd,1H), 2.40 (m, 2H), 2.17 (t, 1H); MS (EI) for C₈H₁₄NO₂CI: 192 (MH⁺).

Hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate: Asuspension of(3R,9aS)-3-(chloromethyl)hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazine(1.97 g, 10.3 mmol) and potassium acetate (10.1 g, 102 mmol) in DMF(20.0 mL) was stirred at 140° C. for 16 h, and then at 150° C. foranother 12 h. The reaction mixture was partitioned between water (250mL) and ethyl acetate (250 mL), the organic layer was washed with 5%lithium chloride (2×100 mL) and brine (100 mL) then dried over anhydroussodium sulfate and concentrated in vacuo. Column chromatography (SiO₂,1:1 hexane:ethyl acetate, then 100% ethyl acetate) afforded 0.92 g (42%)of hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate as ayellow oil. Distinct diastereomers as described above were converted inthis step to give:(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate:¹H NMR (400 MHz, CDCl₃): 4.18 (dd, 1H), 4.00 (m, 1H), 3.80 (dd, 1H),3.68 (dt, 1H), 3.60 (dd, 1H), 3.46 (m, 2H), 3.22 (t, 1H), 2.64 (dd, 1H),2.53 (m, 2H), 2.43-2.35 (m, 2H), 2.10 (s, 3H), and(3S,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate:¹H NMR (400 MHz, CDCl₃): 4.09 (d, 2H), 3.90-3.82 (m, 2H), 3.75-3.64 (m,3H), 3.27 (t, 1H), 3.18 (t, 1H), 2.69 (dd, 1H), 2.63 (m, 1H), 2.46-2.33(m, 2H), 2.16 (t, 1H), 2.10 (s, 3H).

(3R,9aS)-Hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethylmethanesulfonate: To a solution of(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethyl acetate(0.922 g, 4.28 mmol) in methanol (14.0 mL) was added 1.03 mL (4.50 mmol)of sodium methoxide (25% wt. in methanol) dropwise at room temperature.After 5 min., 1.6 mL (6.43 mmol) of 4.0M hydrogen chloride in dioxanewas added and a pink precipitate formed. The solution was concentratedin vacuo and the pink solid was taken up in 30.0 mL dichloromethane.This slurry was cooled in an ice bath and triethylamine (3.0 mL, 21.5mmol) was added, followed by methanesulfonyl chloride (0.37 mL, 4.71mmol). The resultant yellow solution was stirred for 30 minutes at roomtemperature. The mixture was then partitioned between dichloromethaneand saturated aqueous sodium bicarbonate then the aqueous layer wasextracted (3×50 mL dichloromethane). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated in vacuoto provide crude(3R,9aS)-hexahydro-1H-[1,4]oxazino[3,4-c][1,4]oxazin-3-ylmethylmethanesulfonate which was taken on to the following reaction withoutpurification.

Example 70

(8aR)-6-(Chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine: Asolution of (4R)-1,3-thiazolidin-4-ylmethanol (0.300 g, 2.52 mmol) in2-(chloromethyl)oxirane (2.0 mL, 25.5 mmol) was heated under nitrogen to40° C. for 12 h. The solution was then cooled to room temperature and2-(chloromethyl)oxirane was removed in vacuo. The crude intermediate wascooled in ice, and was taken up in 2.0 mL of concentrated sulfuric acid.The resulting mixture was heated to 200° C. for 0.5 h then pouredcarefully onto wet ice, which was allowed to melt. The aqueous solutionwas carefully made basic using solid sodium bicarbonate and theresulting mixture was filtered using water and 10% methanol in ethylacetate as eluent. The layers were separated and the aqueous layer wasextracted with 10% methanol in ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to give 11.6 mg (2.4% yield) of crude(8aR)-6-(chloromethyl)tetrahydro-1H-[1,3]thiazolo[4,3-c][1,4]oxazine asa mixture of diastereomers which was directly taken on to the next step.

Example 71

1,1-Dimethylethyl(3-endo)-3-{2-[(methylsulfonyl)oxy]ethyl}-8-azabicyclo[3.2.1]octane-8-carboxylate:To a solution of 1,1-dimethylethyl(3-endo)-3-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate(30.3 mg, 1.19 mmol) in dichloromethane (4.0 mL), was addedtriethylamine (0.5 mL, 3.56 mmol) and the solution was cooled to 0° C.under nitrogen. Methanesulfonyl chloride (0.11 mL, 1.42 mmol) was addedslowly and mixture was allowed to warm to room temperature and stirredfor 1 h. The reaction mixture was partitioned between dichloromethaneand water. The aqueous phase was extracted with dichloromethane (2×100mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to provide 35.1 mg (89%) of1,1-dimethylethyl(3-endo)-3-{2-[(methylsulfonyl)oxy]ethyl}-8-azabicyclo[3.2.1]octane-8-carboxylate,which was carried forward for alkylation without purification.

Example 72

N-[3-Fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.Crude cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(6-hydroxy-7-methoxy-quinazolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (333 mg, 0.66 mmol), PS-PPh₃ resin,(loading=2.33 mmol/g, 797 mg, 1.86 mmol), 3-morpholin-4-yl-propan-1-ol(0.26 ml, 1.88 mmol), and DEAD (0.31 ml, 1.91 mmol) were combined inCH₂Cl₂ (10 ml) and stirred at room temperature for 1-2 hrs. The reactionmixture was filtered and the resin thoroughly washed with CH₂Cl₂. Thefiltrate was concentrated in vacuo and the resulting residue wasdissolved in EtOAc and washed with H₂O (4×) and sat'd NaCl (1×) and thenextracted with 1N HCl (3×). The combined 1N HCl extractions were washedwith EtOAc (2×). The acidic aqueous phase was then basified with 1N NaOHand extracted with EtOAc (3×). The combined EtOAc extractions werewashed with H₂O (1×), sat'd NaCl (1×), dried (Na₂SO₄), and concentratedin vacuo. The resulting residue was purified by preparative reversephase HPLC (25 mM NH₄OAc/acetonitrile) and the pure fractions werelyophilized to give cyclopropane-1,1-dicarboxylic acid{3-fluoro-4-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide (42.6 mg, 10%). ¹H NMR (400 MHz, DMSO-d₆): δ10.37 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.84 (m, 1H), 7.65 (m,2H), 7.58 (s, 1H), 7.43 (m, 3H), 7.16 (t, 2H), 4.27 (m, 2H), 4.00 (s,3H), 3.60 (m, 6H), 2.39 (m, 4H), 1.99 (m, 2H), 1.47 (m, 4H). LC/MS Calcdfor [M+H]⁺ 634.2, found 634.1.

Using the same or analogous synthetic techniques and/or substitutingwith alternative starting materials, the following were prepared:

N-{3-fluoro-4-[(7-(methyloxy)-6-{[(1-methylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:¹H NMR (400 MHz, CDCl₃): δ 9.67 (s, 1H), 8.59 (s, 1H), 8.43 (s, 1H),7.75 (d, 1H), 7.52 (s, 1H), 7.46 (m, 2H), 7.31 (s, 1H), 7.20 (m, 2H),7.06 (t, 2H), 4.04 (d, 2H), 4.03 (s, 3H), 2.98 (d, 2H), 2.34 (s, 3H),2.12-2.1.95 (m, 5H), 1.76 (m, 2H), 1.64 (m, 2H), 1.57 (m, 2H).

Example 73

Preparation of1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylicacid. To the cyclopropyl di-carboxylic acid (449 mg, 3.45 mmol) in THF(3.5 mL) was added TEA (485 μL, 3.45 mmol). The resulting solution wasstirred at room temperature under a nitrogen atmosphere for 40 minutesbefore adding thionyl chloride (250 μL, 3.44 mmol). The reaction wasmonitored by LCMS for the formation of mono acid chloride (quenched thesample with MeOH and looked for corresponding mono methyl ester). After3 hours stirring at room temperature,4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine (1.02 g, 3.44 mmol) wasadded as a solid, followed by more THF (1.5 mL). Continued to stir atroom temperature for 16 hours. The resulting thick slurry was dilutedwith EtOAc (10 mL) and extracted with 1N NaOH. The biphasic slurry wasfiltered and the aqueous phase was acidified with conc. HCl to pH=6 andfiltered. Both solids were combined and washed with EtOAc, then driedunder vacuum. The desired product,1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylicacid, was obtained (962 mg, 68.7% yield, 97% pure) as a white solid. ¹HNMR (D₂O/NaOH): 7.97 (d, 1H), 7.18 (d, 2H), 6.76 (m, 4H), 6.08 (d, 1H),3.73 (s, 3H), 3.56 (s, 3H), 1.15 (d, 4H).

Example 74

′N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[(4-fluorophenyl)methyl]cyclopropane-1,1-dicarboxamide.To a solution of1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylicacid (74.3 mg, 0.182 mmol), 4-Fluoro benzylamine (25 μL, 0.219 mmol),DIEA (90.0 μL, 0.544 mmol) in DMA (1.0 mL) was added HATU (203 mg, 0.534mmol). The resulting solution was stirred at room temperature for 1 hourbefore adding dropwise to water (10 mL) with stirring. The slurry wassonicated, filtered and the solids were washed with 1 N NaOH followed bywater. After air drying, the solids were further purified by prep HPLC,affording′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[(4-fluorophenyl)methyl]cyclopropane-1,1-dicarboxamide(33 mg, 35% yield, 98% pure) as a white solid. ¹H NMR (DMSO, d₆): 10.82(s, 1H), 8.80 (d, 1H), 8.50 (t, 1H), 7.83 (d, 2H), 7.74 (s, 1H), 7.56(s, 1H), 7.30-7.38 (m, 4H), 7.15 (t, 2H), 6.80 (d, 1H), 4.32 (d, 2H),4.04 (s, 3H), 4.03 (s, 3H), 1.42 (s, 4H).

The following compounds were prepared, in a similar manner as above,from the coupling of1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylic acid with a corresponding alkylamine or arylamine.

N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(piperidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide.¹H NMR (DMSO-d₆): 10.62 (s, 1H), 8.79 (d, 1H), 8.24 (t, 1H), 7.83 (d,2H), 7.72 (s, 1H), 7.58 (s, 1H), 7.37 (d, 2H), 6.76 (d, 1H), 4.04 (s,3H), 4.03 (s, 3H), 3.98 (m, 2H), 3.66 (m, 2H), 3.49 (m, 4H), 3.25 (t,2H), 3.13 (br., 2H), 1.42 (d, 4H).

N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(piperidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide.¹H NMR (DMSO-d₆): 10.78 (s, 1H), 10.53 (s, 1H), 8.43 (d, 1H), 8.12 (d,1H), 7.82 (d, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.20-7.28 (m, 3H), 7.15(dd, 1H), 7.01 (td, 1H), 6.35 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.47(s, 2H), 2.17 (br., 4H), 1.49 (m, 4H), 1.41 (m, 4H), 1.32 (br., 2H).

′N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide.¹H NMR (DMSO-d₆): 10.98 (s, 1H), 10.56 (s, 1H), 8.42 (d, 1H), 8.10 (dd,1H), 7.81 (m, 2H), 7.49 (s, 1H), 7.37 (s, 1H), 7.17-7.27 (m, 4H), 7.01(td, 1H), 6.35 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.61 (s, 2H), 2.30(br., 4H), 1.47 (br., 4H), 1.43 (m, 4H).

′N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(morpholin-4-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide.¹H NMR (DMSO-d₆): 10.12 (s, 1H), 10.03 (s, 1H), 8.44 (d, 1H), 7.74 (d,2H), 7.57 (s, 1H), 7.53 (d, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.21 (m,3H), 6.98 (d, 1H), 6.40 (d, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.56 (t,4H), 3.41 (s, 2H), 2.34 (br., 4H), 1.48 (s, 4H).

′N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[2-(morpholin-4-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide.¹H NMR (DMSO-d₆): 10.54 (s, 1H), 10.47 (s, 1H), 8.43 (d, 1H), 8.08 (d,1H), 7.78 (d, 2H), 7.49 (s, 1H), 7.37 (d, 1H), 7.18-7.30 (m, 4H), 7.03(t, 1H), 6.37 (d, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.50 (s, 2H), 3.44(br., 4H), 2.20 (br., 4H), 1.48 (d, 4H).

′N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(piperidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide.¹H NMR (DMSO-d₆): 10.0-10.2 (br., 2H), 8.46 (d, 1H), 7.76 (d, 2H), 7.53(m, 3H), 7.39 (s, 1H), 7.24 (m, 3H), 6.98 (d, 1H), 6.43 (d, 1H), 3.95(s, 3H), 3.93 (s, 3H), 3.37 (s, 2H), 2.31 (br., 4H), 1.48 (m, 8H), 1.39(br., 2H).

′N-(4-{[6,7-Bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-[3-(pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1-dicarboxamide.¹H NMR (DMSO-d₆): 10.0-10.2 (br., 2H), 8.46 (d, 1H), 7.77 (d, 2H), 7.59(s, 1H), 7.53 (d, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 7.23 (m, 3H), 6.99(d, 1H), 6.43 (d, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.52 (s, 2H), 2.42(br., 4H), 1.69 (br, 4H), 1.48 (s, 4H).

Example 75

Synthesis ofN-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenylcyclopropane-1,1-dicarboxamide Commercially available5-(bis-methylsulfanyl-methylene)-2,2-dimethyl-[1,3]dioxane-4,6-dione(3.5 g, 14 mmol) and 3,4-dimethoxyoaniline (2.2 g, 14 mmol) were refluxin EtOH (20 mL) for 2 hours. The EtOH was removed under reduced pressureand EtOAc was added to the residue. The product was filtered and washedwith cold EtOAc (3×).5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dionewas obtained as a white solid (1.7 g, 47% yield) and used withoutfurther purification. LCMS: m/z 352 (M−H)⁻.

A mixture of5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(1.7 g, 6.6 mmol) and diphenylether (3.5 g, 21 mmol) were heated at 260°C. for 10 minutes. The mixture was cooled to room temperature andheptane was added. 6,7-Dimethoxy-2-methylsulfanyl-quinolin-4-ol wasfiltered and isolated as an orange solid and used without furtherpurification (1.4 g, 83% yield). LCMS: m/z 352 (M+H)⁺.

A mixture of 6,7-dimethoxy-2-methylsulfanyl-quinolin-4-ol (1.0 g, 4.0mmol), 3,4-difluoronitrobenzene (0.48 mL, 4.3 mmol), cesium carbonate(2.6 g, 8.0 mmol), and DMF (15 mL) was stirred at room temperature for12 hours, after which time, the mixture was filtered. The filtrate wasextracted with DCM, washed with 10% LiCl(aq.), water, (1×) and brine(1×), followed by drying over Na₂SO₄ and concentration in vacuo. Thecrude solids were purified by flash chromatography (silica gel, 5% MeOHin DCM), affording the nitroquinoline (1.3 g, 85.8% yield) as an orangesolid. LCMS: m/z 391 (M+H)⁺. A mixture of nitroquinoline (0.33 g, 0.85mmol), 5% Pt/S on carbon (0.050 g), ammonium formate (0.40 g, 6.3 mmol)in EtOH (5 mL) was heated at 80° C. for 1 hour The mixture was cooled toroom temperature and the solvent removed under reduced pressure. Theresidue was dissolved in DCM, the mixture filtered, and the precipitatediscarded. Removal of the organic solvent afforded4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamineas an orange oil (220 mg, 73% yield). LCMS: m/z 361 (M+H)⁺.

To a mixture of4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine(0.22 g, 0.61 mmol) and1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.16 g, 0.73mmol) in DMF (5 mL) was added TEA (0.25 mL, 1.8 mmol) followed by HATU(0.57 g, 1.5 mmol). The resulting solution was stirred overnight at roomtemperature. The reaction mixture was dumped into water and extractedwith DCM (2×). The combined extracts were washed with 5% LiCl(aq) (3×),water, (1×) and brine (1×), followed by drying over Na₂SO₄ andconcentration in vacuo. The crude solids were purified by preparatoryHPLC with ammonium acetate, affordingN-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(0.39 g, 11% yield) as a white solid. ¹H NMR (DMSO-d₆) δ 10.34 (s, 1H),9.94 (s, 1H), 7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 7.40 (m, 2H),7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H),2.48 (s, 3H), 1.40 (m, 4H).

Example 76

Synthesis ofN-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.A mixture of5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(1.0 g, 2.8 mmol), 30% ammonium hydroxide (8.5 mL), HgCl₂ (0.76 g, 2.8mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. Themixture was extracted with DCM and water (3×) and dried with Na₂SO₄.Concentration in vacuo afforded5-[amino-(3,4-dimethoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dioneas a white solid (0.90 g, 97% yield) and this compound was used withoutfurther purification. LCMS: m/z 321 (M−H)⁻.

A mixture of5-[amino-(3,4-dimethoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(0.90 g, 2.8 mmol) and diphenylether (3.0 g, 18 mmol) was heated at 260°C. for 30 minutes. The mixture was cooled to room temperature andheptane was added. Product 2-amino-6,7-dimethoxy-quinolin-4-ol wasfiltered and isolated as an orange solid and used without furtherpurification (0.31 g, 33% yield). LCMS: m/z 221 (M+H)⁺.

4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine wassynthesized from 2-amino-6,7-dimethoxy-quinolin-4-ol in a similar manneras4-(6,7-dimethoxy-2-methylsulfanyl-quinolin-4-yloxy)-3-fluoro-phenylamine,and obtained as a white solid (4.0% yield). LCMS: m/z 330 (M+H)⁺.

N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidewas synthesized from4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine in asimilar manner asN-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.It was purified by preparatory HPLC using ammonium acetate and isolatedas a white solid (4.0% yield). ¹H NMR (DMSO-d₆) δ 10.34 (s, 1H), 9.95(s, 1H), 7.82 (d, 1H), 7.58 (m, 2H), 7.44 (d, 1H), 7.33 (t, 1H), 7.25(s, 1H), 7.09 (t, 2H), 7.07 (s, 1H), 6.17 (br s, 2H), 5.66 (s, 1H), 3.79(s, 3H), 3.77 (s, 3H), 1.40 (d, 4H). LCMS: m/z 535 (M+H)⁺.

Example 77

Synthesis of′N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.A mixture of5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(0.50 g, 1.4 mmol), methylamine (2 M in THF, 0.75 mL. 1.5 mmol), HgCl₂(0.38 g, 1.4 mmol) in THF (5 mL) was stirred at room temperature for 30minutes. The mixture was extracted with DCM and water (3×) and driedwith Na₂SO₄. Concentration in vacuo afforded5-[(3,4-dimethoxy-phenylamino)-methylamino-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dioneas a yellow solid (0.48 g, 99% yield) and this compound was used withoutfurther purification. LCMS: m/z 335 (M−H)⁻.

A mixture of5-[(3,4-dimethoxy-phenylamino)-methylamino-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione(0.40 g, 2.8 mmol) and diphenylether (3.0 g, 18 mmol) was heated at 260°C. for 15 minutes. The mixture was cooled to room temperature andheptane was added. Product 6,7-dimethoxy-2-methylamino-quinolin-4-ol wasfiltered and isolated as a tan solid and used without furtherpurification (0.30 g, quantitative yield). LCMS: m/z 235 (M+H)⁺.

[4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-yl]-methyl-aminewas synthesized from 6,7-dimethoxy-2-methylamino-quinolin-4-ol in asimilar manner as4-(4-Amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine, andisolated as a yellow oil (58% yield). LCMS: m/z 330 (M+H)⁺.

′N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidewas synthesized from[4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-yl]-methyl-aminein a similar manner asN-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide.It was purified by preparatory HPLC using ammonium acetate and isolatedas a white solid (6.0 mg, 4.0% yield). ¹H NMR (DMSO-d₆) δ 10.42 (s, 1H),9.91 (s, 1H), 7.88 (dd, 1H), 7.56 (m, 2H), 7.44 (m, 4H), 7.09 (t, 2H),5.90 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.39 (br s, 1H), 2.92 (s, 3H),1.41 (dt, 4H). LCMS: m/z 535 (M+H)⁺.

Example 78

′N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.To a slurry of cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(6-hydroxy-7-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (0.12 g, 0.23 mmol), hydroxypropyldiethylamine(0.090 mL, 0.61 mmol), triphenylphosphine (0.20 g, 0.76 mmol) in DCM (10mL) was added DIAD (0.17 mL, 0.86 mmol). The resulting mixture wasstirred at room temperature for 12 hours, after which time, the solventwas removed under reduced pressure. The residue was extracted with EtOAcand 1N HCl (6×) and brine (1×) followed by drying with Na₂SO₄.Concentration of the organic fraction in vacuo afforded′N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas a yellow oil (0.18 g, wet, ca 95% purity by analytical HPLC). Furtherpurification by preparatory HPLC using ammonium acetate afforded theproduct in 99% purity by analytical HPLC. LCMS: m/z 619 (M+H)⁺. ¹H NMR(DMSO-d₆) δ 10.37 (br s, 1H), 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H),7.62 (m, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 6.40 (d, 1H),4.17 (t, 2H), 3.93 (s, 3H), 2.59 (t, 2H), 2.49 (m, 6H), 1.91 (m, 4H),0.94 (t, 6H).

Example 79

′N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide.Commercially available 2-amino-4,5-dimethoxy-benzoic acid methyl ester(3 g, 0.014 mol) and acetic anhydride (4.03 mL, 0.0426 mol) were heatedin heptane at 100° C. for 3 hours. After removal of heptane in vaccuo,the crude product of 2-acetylamino-4,5-dimethoxy-benzoic acid methylester was obtained and used without further purification. LC/MS: m/z 254(M+H).

To the crude 2-acetylamino-4,5-dimethoxy-benzoic acid methyl esterobtained above was added ammonium acetate (7.98 g, 0.104 mol) and aceticacid (10 mL). The mixture was heated at reflux in a pressure tube untilthe formation of the desired cyclization product, as indicated by LC/MS:m/z 221 (M+H). After cooling to RT, the reaction mixture was dilutedwith water, and extracted with EtOAc 3 times. The combined organic phasewas basified with aq. NaOH solution, and washed 3 times with EtOAc. Theaqueous layer was then acidified with aq. HCl and extracted three timeswith EtOAc. The combined organic extract was dried over Na₂SO₄ andconcentrated in vacuo, affording 6,7-dimethoxy-2-methyl-quinazolin-4-ol(0.15 g), which was used without further purification. LC/MS: m/z 221(M+H).

A mixture of 6,7-dimethoxy-2-methyl-quinazolin-4-ol obtained fromprevious step (0.15 g, 0.68 mmol) and POCl₃ (1.59 mL, 17.04 mmol) washeated at reflux for 48 hours. The reaction mixture was poured into icewater, neutralized with NaHCO₃, and adjusted to basic with K₂CO₃. Themixture was cooled to 0° C. with stirring. The resulting precipitate wasfiltered, giving 4-chloro-6,7-dimethoxy-2-methyl-quinazoline (0.094 g),which was used without further purification.

A mixture of the chloro quinazoline (0.094 g, 0.397 mmol) obtainedabove, 4-nitrophenol (0.11 g, 0.795 mmol) and bromobenzene (3 mL) washeated at 160° C. for 48 hours. The solvent was then removed and thereaction was taken up in MeOH. Et₂O was added and the reaction stirred30 min and the precipitate was filtered, affording6,7-dimethoxy-2-methyl-4-(4-nitro-phenoxy)-quinazoline (0.081 g) as avery light yellow solid. LC/MS: m/z 342 (M+H).

A mixture of 6,7-dimethoxy-2-methyl-4-(4-nitro-phenoxy)-quinazoline(0.081 g, 0.236 mmole), Pt/S (0.008 g, 15 mol %), ammonium formate(0.098 g, 1.56 mmol) and EtOH (3 mL) was heated with stirring at 70° C.for 3 hours. The reaction mixture was then filtered while hot and washedwith hot EtOH. The crude product of4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (0.924 g) wasobtained as a yellow solid, which was used in the next reaction withoutfurther purification. LC/MS: m/z 312 (M+H).

To a mixture of4-(6,7-dimethoxy-2-methyl-quinazolin-4-yloxy)-phenylamine (0.100 g,0.321 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid(0.056 g, 0.386 mmol) in DMF was added DIEA (0.168 mL, 0.963 mmol),followed by HATU (0.183 g, 0.482 mmol). The reaction mixture was stirredat RT for 15 hours. The mixture was diluted with EtOAc, washed with 5%LiCl aq solution three times, dried over Na₂SO₄, and concentrated invacuo. The crude product was purified on preparative HPLC to give′N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7-bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide(3.2 mg) as a white solid. ¹H NMR (DMSO-d₆) 10.15 (bs, 1H), 10.01 (bs,1H), 7.69-7.75 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (s, 1H), 7.32 (s, 1H),7.23-7.29 (m, 2H), 7.12-7.19 (m, 2H), 3.93 (d, 6H), 2.43 (s, 3H), 1.53(s, 4H).

Example 80

Preparation of1-(4-Fluoro-phenylcarbamoyl)-2-methyl-cyclopropanecarboxylic acid.2-Methylcyclopropane-1,1-dicarboxylic acid methyl ester was prepared byfollowing the literature procedure (Baldwin, J. E.; Adlington, R. M.;Rawlings, B. J. Tetrahedron Lett. 1985, 481.) The carboxylic acid (700mg, 4.4 mmol) was dissolved in CH₂Cl₂ (10 mL). To the resulting solutionwas added 4-fluoroaniline (590 mg, 5.3 mmol), HOBt (890 mg, 6.6 mmol)and EDCI (2.5 g, 13.2 mmol). The stirring was continued for 3 h at rt.CH₂Cl₂ (30 mL) was added to the reaction mixture, and the resultingsolution was washed with brine, and dried over Na₂SO₄. CH₂Cl₂ wasremoved under reduced pressure. Further purification by columnchromatography gave 635 mg (57%) of the desired amide.

The methyl ester obtained above was then treated with LiOH.H₂O (116 mg,2.78 mmol, 1.1 eqiv.) in THF (2 mL) and H₂O (1 mL) for 3 h at rt. THFwas removed under reduced pressure. The aqueous solution was dilutedwith 20 mL of H₂O, washed with ether (10 mL), and acidified with 1 NHCl. The solid was filtered, dissolved in EtOAc, and dried over Na₂SO₄.Removal of EtOAc gave the crude product of1-(4-fluoro-phenylcarbamoyl)-2-methyl-cyclopropane-carboxylic acid,which was used in the next reaction. ¹H NMR (400 MHz, DMSO-d₆) δ 12.99(br s, 1H), 10.33 (br s, 1H), 7.59 (dd, J=9.0, 5.0 Hz, 2H), 7.11 (dd,J=9.0, 9.0 Hz, 2H), 1.86-1.78 (m, 1H), 1.43 (dd, J=9.0, 4.2 Hz, 1H),1.30 (dd, J=7.8, 4.3 Hz, 1H), 1.19 (d, J=6.3 Hz, 3H).

Example 81

Synthesis of(1S,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide.To a solution of4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (150 mg,0.38 mmol) in CH₂Cl₂ (3 mL) was added DIEA (341 mg, 2.64 mmol),1-(4-fluoro-phenylcarbamoyl)-2-methyl-cyclopropanecarboxylic acid (120mg, 0.49 mmol) and PyBOP (686 mg, 1.32 mmol). The reaction mixture wasstirred at rt for 6 h. After standard workup, the crude product waspurified by column chromatography.

The coupling product (130 mg, 0.21 mmol) obtained above was dissolved inEtOH (2 mL). 1,4-cyclohexadiene (170 mg, 2.1 mmol) and 10% Pd/C (10 mg)were added. The mixture was stirred for 2 h under reflux. After cooling,the mixture was filtered through Celite, and washed with MeOH. Removalof the solvents gave the crude product (136 mg), which was used in thenext reaction.

To a solution of the 7-hydroxyquinoline (136 mg, 0.26 mmol) in DMF (2mL) was added 4-(3-chloropropyl)morpholine hydrochloride (70 mg, 0.35mmol) and K₂CO₃ (69 mg, 0.50 mmol). The reaction mixture was thenstirred at 80° C. for 5 h. After cooling, EtOAc (20 mL) was added. TheEtOAc solution was washed twice with brine, and dried over Na₂SO₄.Removal of EtOAc and purification by column chromatography (CH₂Cl₂:MeOH=10:1) gave′(1S,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide.The product was then dissolved in ethyl ether, and treated with 1.5equiv. of 1 N HCl/ether. Filtration and lyophilization gave the HCl saltof′(1S,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide:¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (br s, 1H), 10.26 (br s, 1H), 10.15(br s, 1H), 8.74 (br s, 1H), 7.95 (br d, J=13.2 Hz, 1H), 7.8-7.5 (m,6H), 7.16 (t, J=8.9 Hz, 2H), 6.82 (br s, 1H), 4.34 (t, J=5.9 Hz, 2H),4.02 (s, 3H), 3.99 (br s, 2H), 3.77 (br t, J=12.0 Hz, 2H), 3.56-3.30 (m,4H), 3.17-3.07 (m, 2H), 2.40-2.30 (m, 2H), 2.04-1.95 (m, 1H), 1.45 (dd,J=7.2, 4.7 Hz, 1H), 1.36 (dd, J=8.5, 4.5 Hz, 1H), 1.09 (d, J=6.2 Hz,3H).

Example 82

Synthesis of(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide.To a solution of4-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (322 mg,0.82 mmol) and 2-Methyl-cyclopropane-1,1-dicarboxylic acid methyl ester(195 mg, 1.23 mmol) in CH₂Cl₂ (4 mL) was added HOBt (61 mg, 0.32 mmol)and EDCI (211 mg, 1.64 mmol). The stirring was continued for 12 h at rt.The reaction mixture was then diluted with EtOAc and washed with brine.Removal of organic solvents in vacuo and further purification by columnchromatography gave the desired coupling product (153 mg).

The product (153 mg, 0.29 mmol) obtained above was treated with LiOH.H₂O(15 mg, 0.35 mmol) in THF (1 mL) and H₂O (1 mL) for 2 h. THF wasremoved. 10 mL of H₂O was added to the mixture. The aqueous solution waswashed with ether, and acidified with 1 N HCl. The solid was thenfiltered and dried under vacuum.

The crude carboxylic acid (118 mg, 0.23 mmol) and 4-fluoroaniline (111mg, 0.27 mmol) were dissolved in DMF (2 mL). To this solution was addedDIEA (178 mg, 1.38 mmol) and PyBOP (358 mg, 0.69 mmol). The mixture wasstirred overnight at rt. It was then diluted with EtOAc, washed twicewith brine. Removal of EtOAc and column chromatography gave the desiredproduct.

The product (66 mg, 0.11 mmol) obtained above was dissolved in EtOH (2mL). 1,4-cyclohexadiene (80 mg, 1.1 mmol) and 10% Pd/C (10 mg) wereadded. The mixture was stirred for 2 h under reflux. After cooling, themixture was filtered through Celite, and washed with MeOH. Removal ofthe solvents gave the crude product (70 mg), which was used in the nextreaction.

To a solution of the 7-hydroxyquinoline (80 mg, 0.15 mmol) in DMF (2 mL)was added 4-(3-chloropropyl)morpholine hydrochloride (62 mg, 0.31 mmol)and K₂CO₃ (64 mg, 0.46 mmol). The reaction mixture was then stirred at80° C. for 5 h. After cooling, EtOAc (20 mL) was added. The EtOAcsolution was washed twice with brine, and dried over Na₂SO₄. Removal ofEtOAc and purification by column chromatography (CH₂Cl₂: MeOH=10:1) gave′(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide.The product was then dissolved in ethyl ether, and treated with 1.5equiv. of 1 N HCl/ether. Filtration and lyophilization gave the HCl saltof′(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide:¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (br s, 1H), 10.54 (br s, 1H), 9.74 (s,1H), 8.75 (br s, 1H), 8.01 (br d, J=12.9 Hz, 1H), 7.80-7.50 (m, 6H),7.20-7.10 (m, 2H), 6.84 (br s, 1H), 4.34 (br t, J=5 Hz, 2H), 4.04 (s,3H), 4.05-3.95 (m, 2H), 3.77 (br t, J=11 Hz, 2H), 3.52 (br d, J=12.7 Hz,4H), 3.12 (br q, J=9.0 Hz, 2H), 2.40-2.30 (m, 2H), 2.10-1.95 (m, 1H),1.40-1.30 (m, 2H), 1.10 (d, J=6.2 Hz, 3H).

Example 83

Synthesis of′(2R,3R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide.2,3-trans-Dimethyl-cyclopropane-1,1-dicarboxylic acid diethyl ester wasprepared by following the literature procedure. (Ohishi, J. Synthesis,1980, 690.) To a solution of2,3-trans-dimethyl-cyclopropane-1,1-dicarboxylic acid diethyl ester(6.75 g, 31.5 mmol) in MeOH (30 mL) was added 33 mL of 1 N NaOH aqueoussolution. The mixture was stirred at 85° C. for 5 h. MeOH was removedunder reduced pressure; the residue was diluted with 40 mL of H₂O. Theaqueous solution was washed with 20 mL of ether, and acidified with 1 NHCl. Filtration and drying under vacuum gave 4.72 g 80%) of the desiredcarboxylic acid.

The aniline (1.08 g, 2.78 mmol) and the carboxylic acid (518 mg, 2.78mmol) prepared above were dissolved in CH₂Cl₂ (15 mL). HATU (2.11 g,5.56 mmol) and DIEA (1.8 mL, 11.1 mmol) were added. The reaction mixturewas stirred at rt overnight. It was then concentrated and diluted withEtOAc. The EtOAc solution was then washed with 5% NaOH and brine.Removal of EtOAc gave the crude coupling product, which was hydrolyzedto the corresponding carboxylic acid by treatment with LiOH.H₂O (175 mg,4.17 mmol) in THF (100 mL)-H₂O (50 mL) at 60° C. for 10 h.

The carboxylic acid (850 mg, 1.60 mmol) and 4-fluoroaniline (355 mg,3.20 mmol) were dissolved in DMF (8 mL). HATU (3.89 g, 3.2 mmol) andDIEA (1.1 ml, 6.4 mmol) were added. The reaction mixture was stirred atrt overnight. H₂O (10 mL) was added to the reaction, and a precipitateformed. The solid was filtered, washed with aqueous sat. Na₂CO₃ andether. Further purification by column chromatography gave 596 mg (60%)of the desired product. Debenzylation was done by following the standardprocedure.

To a solution of the 7-hydroxyquinoline (261 mg, 0.49 mmol) in DMF (5mL) was added 4-(3-chloropropyl)morpholine hydrochloride (195 mg, 0.98mmol) and K₂CO₃ (202 mg, 1.46 mmol). The reaction mixture was thenstirred at 80° C. for 4 h. After cooling, EtOAc (20 mL) was added. TheEtOAc solution was washed twice with brine, and dried over Na₂SO₄.Removal of EtOAc and purification by column chromatography (CH₂Cl₂:MeOH=10:1) gave 122 mg (37%) of′(2R,3R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethyl-cyclopropane-1,1-dicarboxamide.¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=5.1 Hz, 1H), 8.11 (br s, 1H),7.77-7.70 (m, 2H), 7.53 (s, 1H), 7.50-7.44 (m, 2H), 7.40 (s, 1H),7.22-7.16 (m, 2H), 7.06-6.98 (m, 2H), 6.36 (br d, J=5.1 Hz, 1H), 4.26(t, J=7.0 Hz, 2H), 4.02 (s, 3H), 3.72 (t, J=4.4 Hz, 4H), 2.57 (t, J=7.3Hz, 2H), 2.50-2.42 (m, 4H), 2.18-2.10 (m, 2H), 1.80-1.66 (m, 2H),1.30-1.24 (m, 6H).

Example 84

Synthesis of′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide.1-Benzyl-azetidine-3,3-dicarboxylic acid was prepared by following theliterature procedure (Miller, R. A.; et al. Syn. Comm. 2003, 33, 3347).To a solution of 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine (4.2mmol, 1 equiv.) and 4-fluoroaniline (4.2 mmol, 1 equiv.) in DMF (20 mL)was charged with DIEA (12.6 mmol, 3 equiv.) and a solution of1-benzyl-azetidine-3,3-dicarboxylic acid (4.2 mmol, 1 equiv.) in DMF (10mL). The reaction mixture was allowed to stir at RT and monitored byLCMS. The reaction was complete in 6 h. The reaction mixture was dilutedwith ethyl acetate and washed with 10% LiCl (3×), brine (3×), dried withsodium sulfate, filtered and the solvent was reduced in vacuo. The crudeproduct was purified by silica gel chromatography eluting with 2% ofMeOH in EtOAc. The fractions containing the desired product were furtherpurified using preparative HPLC to give′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide(300 mg, 12% yield) as a white solid. ¹HNMR (DMSO-d₆): 10.0 (s, 1H),9.90 (s, 1H), 8.45 (d, 1H), 7.80 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H),7.40 (s, 1H), 7.48-7.15 (m, 9H), 3.95 (s, 6H), 3.70 (s, 4H), 3.60 (s,2H). LCMS (POS): 607.2 (M+H).

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)azetidine-3,3-dicarboxamide. To a solution of′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide(300 mg, 0.5 mmol) in MeOH (50 mL) was charged with Pd/C (50% wet, 10%mmol, 265 mg) and acetic acid (2 mL). The reaction mixture was subjectedto hydrogenolysis condition under H2 (50 psi) on a Parr Hydrogenator for16 hr. The reaction mixture was filtered through celite and washed withMeOH. After removal of solvent in vacuo, the crude product was purifiedusing preparative HPLC (solvent system: MeCN/H₂O/NH₄OAc), affordingN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)azetidine-3,3-dicarboxamide (82 mg, 32% yield) as a white solid. ¹HNMR(DMSO-d₆): 8.46 (d, 1H), 7.84 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40(s, 1H), 7.24 (d, 2H), 7.20 (t, 2H), 6.44 (d, 1H), 4.03 (s, 4H), 3.95(s, 6H), 1.90 (s, 3H, acetate salt). LCMS (POS): 517.3 (M+H).

Example 85

N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.To a solution of cyclopropane-1,1-dicarboxylic acid{3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-amide(4-fluoro-phenyl)-amide, TFA salt (˜500 mg, 0.71 mmol) in ClCH₂H₂Cl (8mL) were added 30% formaldehyde (4 mL) and NaBH(OAc)₃ (752 mg, 3.55mmol). The reaction mixture was stirred overnight. It was then quenchedwith aqueous sat. NaHCO₃, extracted with EtOAc. The organic phase waswashed with brine and dried over Na₂SO₄. Drying salts were filtered,washed with EtOAc and the filtrate concentrated in vacuo to give 21 0mgs of crude product. The resulting residue was redissolved in EtOAc andany insoluble material filtered. To the filtrate was added 4M HCl indioxane (200 μl) and the mixture was stirred at room temperature for 1hour. Solids were filtered, washed with EtOAc, dried under high vacuum,dissolved in 50% aqueous AcCN and lyophilized to give′N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,HCl salt (113 mg, 25% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H),10.30 (br. s, 1H), 10.04 (s, 1H), 8.80 (d, 1H), 7.99 (dd, 1H), 7.55 (m,2H), 7.67-7.53 (m, 4H), 7.16 (t, 2H), 6.89 (d, 1H), 4.13 (d, 2H), 4.05(s, 3H), 3.47 (m, 2H), 3.00 (m, 2H), 2.74 (d, 3H), 2.17 (m, 1H), 2.03(m, 2H), 1.68 (m, 2H), 1.49 (m, 4H). LC/MS Calcd for [M+H]⁺ 617.3, found617.4. Anal. HPLC (8 min gradient): 98% pure, 3.11 min.

Example 86

(1R,2R,3S)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide.2,3-Dimethyl-cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (210 mg, 0.39 mmol), DMA (2 mls),(2-chloro-ethyl)-diethyl-amine, HCl salt (73 mg, 0.42 mmol) and K₂CO₃(136 mg, 0.98 mmol) were combined and heated at 80 C overnight. Thereaction mixture was then diluted with H₂O and sonicated. The resultingsolids were filtered, washed with H₂O and dried under high vacuum. Thecrude product was then purified by preparative HPLC using an ammoniumacetate buffer system and lyophilized to give′(1R,2R,3S)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide(39 mg, 16% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 10.14 (s, 1H), 9.61 (s,1H), 8.46 (d, 1H), 7.87 (dd, 1H), 7.67 (m, 2H), 7.57 (m, 1H), 7.51 (s,1H), 7.42 (s, 1H), 7.39 (m, 1H), 7.15 (t, 2H), 6.41 (d, 1H), 4.20 (m,2H), 3.94 (s, 3H), 2.87 (m, 2H), 2.60 (m, 4H), 1.80 (m, 2H), 1.18 (s,3H), 1.17 (s, 3H), 1.01 (m, 6H). Note: 0.5 eq of AcOH is present by NMR.LC/MS Calcd for [M+H]⁺ 633.3, found 633.4. Anal. HPLC (25 min gradient):96% pure, 18.52 min.

Example 87

N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1-dicarboxamide.2,2-Dimethyl-cyclopropane-1,1-dicarboxylic acid[3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (203 mg, 0.38 mmol), DMA (2 mls),(2-chloro-ethyl)-diethyl-amine, HCl salt (73 mg, 0.42 mmol) and K₂CO₃(146 mg, 1.05 mmol) were combined and heated at 80 C overnight. Thereaction mixture was then diluted with H₂O and extracted with CH₂Cl₂(3×). The combined CH₂Cl₂ extractions were washed with sat'd NaHCO₃(1×), sat'd NaCl (1×), dried (Na₂SO₄), and concentrated in vacuo. Theresulting crude product was purified by flash chromatography (Silica Gel60, 100% EtOAc, followed by 10% MeOH, 1% triethylamine in EtOAc), thendissolved in 50% aqueous AcCN and lyophilized to give′N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethyl-cyclopropane-1,1-dicarboxamide(70 mg, 29% yield). ¹H NMR (400 MHz, DMSO): δ 10.24 (s, 1H), 10.00 (s,1H), 8.54 (s, 1H), 7.84 (dd, 1H), 7.66 (m, 2H), 7.56 (s, 1H), 7.51 (m,1H), 7.43 (m, 2H), 7.18 (t, 2H), 4.26 (m, 2H), 3.98 (s, 3H), 2.88 (m,2H), 2.59 (m, 4H), 1.58 (m, 2H), 1.18 (s, 6H), 1.00 (t, 6H). LC/MS Calcdfor [M+H]⁺ 634.3, found 634.4. Anal. HPLC (25 min gradient): 94% pure,24.08 min.

Example 88

Synthesis of′N-[3-(aminomethyl)phenyl]-N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide.(4-Nitro-benzyl)-carbamic acid tert-butyl ester. 4-Nitro-benzylamine,HCl salt (5.19 g, 27.5 mmol) was dissolved in dioxane (100 mls). NaOH(3.4 g, 85.0 mmol) in H₂O (20 mls) was added, followed by Boc anhydride(7.6 g, 34.8 mmol). The mixture was stirred at room temperature. After 3hrs, the reaction mixture was diluted with EtOAc and washed with H₂O(3×), sat'd NaCl (1×), dried (Na₂SO₄), and concentrated in vacuo. Theresulting residue was triturated with hexanes, the resulting solidsfiltered, washed with hexanes and dried under vacuum to give(4-nitro-benzyl)-carbamic acid tert-butyl ester (6.34 g, 91% yield).LC/MS Calcd for [M+H]⁺ 253.1, found 197.0 (minus t-butyl).

(4-Amino-benzyl)-carbamic acid tert-butyl ester.(4-Nitro-benzyl)-carbamic acid tert-butyl ester (6.34 g, 25.1 mmol),iron powder (6.5 g, 116 mmol), ammonium formate (13.0 g, 206 mmol), H₂O(75 mls), and toluene (75 mls) were combined and heated to reflux. After3 hrs the reaction mixture was allowed to cool and filtered throughCelite with thorough washing with EtOAc. The filtrate was transferred toa separatory funnel and the phases separated. The organic phase wasfurther washed with H₂O (1×), sat'd NaCl (1×), dried (Na₂SO₄), andconcentrated in vacuo to give (4-amino-benzyl)-carbamic acid tert-butylester (5.02 g, 90% yield). LC/MS Calcd for [M+H]⁺ 223.1, found 167.1(minus t-butyl).

[3-({1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropane-carbonyl}-amino)-benzyl]-carbamicacid tert-butyl ester.1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarboxylicacid (254 mg, 0.62 mmol), (4-amino-benzyl)-carbamic acid tert-butylester (164 mg, 0.74 mmol), dry DMA (10 mls), HATU (714 mg, 1.88 mmol),and DIEA (325 ml, 1.86 mmol) were combined and stirred at roomtemperature. After 2 hrs, the reaction mixture is diluted with H₂O andthe resulting solids are filtered, washed with H₂O, followed by sat'dNaHCO₃, and dried under high vacuum to give crude[3-({1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarbonyl}-amino)-benzyl]-carbamicacid tert-butyl ester (301 mg, 79% yield) which was used in the nextreaction without further purification. LC/MS Calcd for [M+H]⁺ 613.3,found 613.1.

N-[3-(Aminomethyl)phenyl]-N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide,TFA salt.[3-({1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenylcarbamoyl]-cyclopropanecarbonyl}-amino)-benzyl]-carbamicacid tert-butyl ester (50 mg, 0.081 mmol) was dissolved in 50% TFA inCH₂Cl₂ (10 mls) and stirred at room temperature. After 2 hrs, thereaction mixture was concentrated in vacuo and the resulting residue wastriturated with Et₂O. The resulting solids were filtered, washed withEt₂O and dried under high vacuum to give′N-[3-(aminomethyl)phenyl]-N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamideas the TFA salt (54 mg, 100%). ¹HNMR (400 MHz, DMSO-d₆): δ 10.28 (s,1H), 10.19 (s, 1H), 8.77 (m, 1H), 8.21 (m, 3H), 7.84 (m, 2H), 7.76 (m,1H), 7.71 (m, 1H), 7.58 (m, 2H), 7.38 (m, 3H), 7.19 (m, 1H), 6.76 (m,1H), 4.03 (s, 6H), 3.39 (m, 2H), 1.53 (m, 4H). Note: all peaks are verybroad and unresolved. LC/MS Calcd for [M+H]⁺ 513.2, found 513.4. Anal.HPLC (25 min gradient): 88% pure, 12.39 min.

Table 3 contains ¹H-NMR data for selected compounds of the invention.

TABLE 3 Entry Name ¹H-NMR 1 N-[3-fluoro-4-({6-(methyloxy)- 1H NMR(DMSO-d6): 10.52 (s, 1H), 10.02 (s, 7-[(3-piperazin-1- 1H), 9.38 (br.,3H), 8.79 (d, 1H), 7.98 (dd, 1H), ylpropyl)oxy]quinolin-4- 7.74 (s, 1H),7.65 (m, 3H), 7.54 (m, 2H), yl}oxy)phenyl]-N′-(4- 7.15 (t, 2H), 6.86 (d,1H), 4.33 (t, 2H), 4.04 (s, 3H), fluorophenyl)cyclopropane-1,1-3.17-3.50 (m, 9H), 2.27 (br., 2H), 1.79 (m, 1H), dicarboxamide 1.48 (m,4H). Note: The peak at δ9.38 includes 2 TFA equivalents. 2N-{3-fluoro-4-[(6-(methyloxy)- 1H NMR (DMSO-d6): 10.41 (s, 1H), 10.03(s, 7-{[3-(4-methylpiperazin-1- 1H), 8.47 (d, 1H), 7.90 (dd, 1H), 7.64(m, 2H), yl)propyl]oxy}quinolin-4- 7.52 (s, 2H), 7.42 (t, 1H), 7.39 (s,1H), 7.16 (t, yl)oxy]phenyl}-N′-(4- 2H), 6.41 (d, 1H), 4.18 (t, 2H),3.95 (s, 3H), fluorophenyl)cyclopropane-1,1- 2.47 (t, 2H), 2.6-2.8 (br.,8H), 2.17 (s, 3H), dicarboxamide 1.97 (m, 2H), 1.48 (s, 4H). 3N-{3-fluoro-4-[(6-(methyloxy)- 1H NMR (400 MHz, DMSO-d6): d 10.51 (s,7-{[(1-methylpiperidin-4- 1H), 10.30 (br. s, 1H), 10.04 (s, 1H), 8.80(d, yl)methyl]oxy}quinolin-4- 1H), 7.99 (dd, 1H), 7.55 (m, 2H),7.67-7.53 (m, yl)oxy]phenyl}-N′-(4- 4H), 7.16 (t, 2H), 6.89 (d, 1H),4.13 (d, 2H), fluorophenyl)cyclopropane-1,1- 4.05 (s, 3H), 3.47 (m, 2H),3.00 (m, 2H), dicarboxamide 2.74 (d, 3H), 2.17 (m, 1H), 2.03 (m, 2H),1.68 (m, 2H), 1.49 (m, 4H). 4 N-(4-fluorophenyl)-N′-[4-({6- ¹H NMR (400MHz, DMSO-d6): 8.47 (d, 1H), (methyloxy)-7-[(3-morpholin-4- 8.30 (m,1H), 8.15 (m, 1H), 7.8 (m, 2H), ylpropyl)oxy]quinolin-4- 7.62 (s, 1H),7.45 (m, 2H), 7.2 (m, 3H), 7.10 (m, yl}oxy)phenyl]cyclopropane- 2H), 6.7(d, 1H), 4.5 (m, 2H), 4.3 (m, 2H), 1,1-dicarboxamide 4.01 (s, 3H), 3.5(br, 2H), 3.3 (m, 2H), 3.1 (m, 2H), 2.51 (m, 2H), 1.9 (m, 2H) 1.6 (m,4H). 5 N-(4-{[7-{[3- ¹H NMR (400 MHz, DMSO-d6): 10.58 (s, 1H),(diethylamino)propyl]oxy}-6- 10.31 (bs, 1H), 10.04 (s, 1H), 8.75 (d,1H), (methyloxy)quinolin-4-yl]oxy}- 7.99 (d, 1H), 7.74 (s, 1H), 7.63 (m,4H), 3-fluorophenyl)-N′-(4- 7.19 (t, 2H), 6.91 (m, 1H), 4.39 (t, 2H),4.19 (s, 3H), fluorophenyl)cyclopropane-1,1- 3.21 (m, 7H), 2.29 (m, 2H),1.46 (d, 4H), dicarboxamide 1.15 (t, 6H). 6 N-(4-{[6,7- 1H NMR(DMSO-d6): 11.56 (s, 1H), 9.77 (s, bis(methyloxy)quinolin-4- 1H), 8.50(d, 1H), 8.32 (d, 1H), 7.82 (d, 1H), yl]oxy}-2-chloro-5- 7.59 (m, 2H),7.51 (s, 1H), 7.42 (s, 1H), 7.20 (t, fluorophenyl)-N′-(4- 2H), 6.55 (d,1H), 3.95 (s, 3H), 3.94 (s, 3H), fluorophenyl)cyclopropane-1,1- 1.73 (m,2H), 3.65 (m, 2H). dicarboxamide 7 N-(4-{[6,7-bis(methyloxy)-2- ¹H NMR(DMSO-d₆) d 10.34 (s, 1H), 9.94 (s, (methylthio)quinolin-4-yl]oxy}- 1H),7.83 (d, 1H), 7.59 (m, 2H), 7.56 (m, 1H), 3-fluorophenyl)-N′-(4- 7.40(m, 2H), 7.23 (s, 1H), 7.09 (t, 2H), 6.12 (s,fluorophenyl)cyclopropane-1,1- 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.48 (s,3H), dicarboxamide 1.40 (m, 4H). 8 N-(4-fluorophenyl)-N′-(4-{[2- ¹H NMR(DMSO-d₆) 10.15 (bs, 1H), 10.01 (bs, methyl-6,7-bis(methyloxy) 1H),7.69-7.75 (m, 2H), 7.61-7.68 (m, 2H), quinazolin-4-yl]oxy}phenyl) 7.52(s, 1H), 7.32 (s, 1H), 7.23-7.29 (m, 2H), cyclopropane-1,1- 7.12-7.19(m, 2H), 3.93 (d, 6H), 2.43 (s, 3H), dicarboxamide 1.53 (s, 4H). 9N-(4-{[2-amino-6,7- 1H NMR (DMSO-d6) d 10.34 (s, 1H), 9.95 (s,bis(methyloxy)quinolin-4- 1H), 7.82 (d, 1H), 7.58 (m, 2H), 7.44 (d, 1H),yl]oxy}-3-fluorophenyl)-N′-(4- 7.33 (t, 1H), 7.25 (s, 1H), 7.09 (t, 2H),7.07 (s, fluorophenyl)cyclopropane-1,1- 1H), 6.17 (br s, 2H), 5.66 (s,1H), 3.79 (s, 3H), dicarboxamide 3.77 (s, 3H), 1.40 (d, 4H). 10N-(3-fluoro-4-{[2- ¹H NMR (DMSO-d₆) d 10.42 (s, 1H), 9.91 (s,(methylamino)-6,7- 1H), 7.88 (dd, 1H), 7.56 (m, 2H), 7.44 (m, 4H),bis(methyloxy)quinolin-4- 7.09 (t, 2H), 5.90 (s, 1H), 3.88 (s, 3H), 3.85(s, yl]oxy}phenyl)-N′-(4- 3H), 3.39 (br s, 1H), 2.92 (s, 3H), 1.41 (dt,4H). fluorophenyl)cyclopropane-1,1- dicarboxamide 11(1S,2R)—N-[3-fluoro-4-({6- ¹H NMR (400 MHz, DMSO-d₆) d 10.49 (br s,(methyloxy)-7-[(3-morpholin-4- 1H), 10.26 (br s, 1H), 10.15 (br s, 1H),ylpropyl)oxy]quinolin-4- 8.74 (br s, 1H), 7.95 (br d, J = 13.2 Hz, 1H),yl}oxy)phenyl]-N′-(4- 7.8-7.5 (m, 6H), 7.16 (t, J = 8.9 Hz, 2H), 6.82(br fluorophenyl)-2- s, 1H), 4.34 (t, J = 5.9 Hz, 2H), 4.02 (s, 3H),methylcyclopropane-1,1- 3.99 (br s, 2H), 3.77 (br t, J = 12.0 Hz, 2H),dicarboxamide 3.56-3.30 (m, 4H), 3.17-3.07 (m, 2H), 2.40-2.30 (m, 2H),2.04-1.95 (m, 1H), 1.45 (dd, J = 7.2, 4.7 Hz, 1H), 1.36 (dd, J = 8.5,4.5 Hz, 1H), 1.09 (d, J = 6.2 Hz, 3H). 12 (1R,2R)—N-[3-fluoro-4-({6- ¹HNMR (400 MHz, DMSO-d₆) d 10.65 (br s, (methyloxy)-7-[(3-morpholin-4-1H), 10.54 (br s, 1H), 9.74 (s, 1H), 8.75 (br s,ylpropyl)oxy]quinolin-4- 1H), 8.01 (br d, J = 12.9 Hz, 1H),yl}oxy)phenyl]-N′-(4- 7.80-7.50 (m, 6H), 7.20-7.10 (m, 2H), 6.84 (br s,1H), fluorophenyl)-2- 4.34 (br t, J = 5 Hz, 2H), 4.04 (s, 3H),methylcyclopropane-1,1- 4.05-3.95 (m, 2H), 3.77 (br t, J = 11 Hz, 2H),dicarboxamide 3.52 (br d, J = 12.7 Hz, 4H), 3.12 (br q, J = 9.0 Hz, 2H),2.40-2.30 (m, 2H), 2.10-1.95 (m, 1H), 1.40-1.30 (m, 2H), 1.10 (d, J =6.2 Hz, 3H). 13 N-(4-{[6-{[3- ¹H NMR (DMSO-d₆) d 10.37 (br s, 1H),(diethylamino)propyl]oxy}-7- 10.00 (s, 1H), 8.44 (d, 1H), 7.87 (d, 1H),7.62 (m, (methyloxy)quinolin-4-yl]oxy}- 2H), 7.49 (m, 2H), 7.41 (m, 2H),7.13 (t, 2H), 3-fluorophenyl)-N′-(4- 6.40 (d, 1H), 4.17 (t, 2H), 3.93(s, 3H), 2.59 (t, fluorophenyl)cyclopropane-1,1- 2H), 2.49 (m, 6H), 1.91(m, 4H), 0.94 (t, 6H). dicarboxamide 14 N-(4-{[6-{[2- ¹H NMR (DMSO-d₆) d10.36 (br s, 1H), (diethylamino)ethyl]oxy}-7- 9.99 (s, 1H), 8.44 (d,1H), 7.88 (dd, 1H), 7.62 (m, (methyloxy)quinolin-4-yl]oxy}- 2H), 7.57(m, 2H), 7.41 (m, 2H), 7.13 (t, 2H), 3-fluorophenyl)-N′-(4- 6.40 (d,1H), 4.17 (t, 2H), 3.93 (s, 3H), 2.85 (t, fluorophenyl)cyclopropane-1,1-2H), 2.56 (q, 4H), 2.49 (m, 4H), 0.98 (t, 6H). dicarboxamide 151,1-dimethylethyl 4-(3-{[4-[(2- ¹H NMR (400 MHz, CDCl₃): 10.05 (s, 1H),fluoro-4-{[(1-{[(4- 8.49-8.27 (t, 1H), 7.79-7.76 (d, 1H), 7.57 (s,fluorophenyl)amino]carbonyl}cyclopropyl) 1H), 7.47-7.43 (m, 3H),7.27-7.20 (m, 1H), carbonyl]amino}phenyl) 7.09-7.04 (m, 2H), 6.40-6.39(d, 1H), oxy]-6-(methyloxy) 4.28-4.25 (t, 2H), 3.50 (s, 3H), 3.47-3.44,(t, 4H), quinolin-7-yl]oxy}propyl) 2.62-2.59 (t, 2H), 2.46-2.44 (t, 4H),2.18-2.11 (m, piperazine-1-carboxylate 2H), 2.09 (s, 1H), 1.83-1.81 (t,2H), 1.64-1.61 (t, 2H), 1.47 (s, 9H). 16 (1R,2R)—N-[3-fluoro-4-({6- ¹HNMR (DMSO-d₆) d 10.40 (s, 1H), 9.65 (s, (methyloxy)-7-[(3-morpholin-4-1H), 8.45 (s, 1H), 7.79 (dd, 1H), 7.53 (m, 2H),ylpropyl)oxy]quinazolin-4- 7.47 (s, 1H), 7.36 (m, 1H), 7.31 (m, 2H),yl}oxy)phenyl]-N′-(4- 7.05 (t, 2H), 4.17 (t, 2H), 3.91 (s, 3H), 3.51 (t,4H), fluorophenyl)-2- 2.40 (t, 2H), 2.36 (m, 4H), 1.90 (m, 3H),methylcyclopropane-1,1- 1.30 (m, 2H), 1.02 (d, 3H). dicarboxamide 17(1R,2R)—N-(4-{[7-{[2- ¹H NMR (DMSO-d₆) d 10.49 (s, 1H), 9.73 (s,(diethylamino)ethyl]oxy}-6- 1H), 8.52 (s, 1H), 7.85 (dd, 1H), 7.61 (m,2H), (methyloxy)quinazolin-4- 7.54 (s, 1H), 7.41 (m, 3H), 7.12 (t, 2H),7.23 (t, yl]oxy}-3-fluorophenyl)-N′-(4- 2H), 3.96 (s, 3H), 2.86 (t, 2H),2.56 (q, 4H), fluorophenyl)-2- 1.98 (m, 1H), 1.34 (m, 2H), 1.07 (d, 3H),methylcyclopropane-1,1- 0.97 (t, 6H). dicarboxamide 18 N-(4-{[7-{[3- 1HNMR (DMSO-d6) 8.51 (s, 1H), (diethylamino)propyl]oxy}-6- 7.78-7.84 (m,1H), 7.58-7.64 (m, 2H), 7.53 (s, 1H), (methyloxy)quinazolin-4- 7.34-7.48(m, 3H), 7.13 (t, 2H), 4.22 (t, 2H), 3.98 (s,yl]oxy}-3-fluorophenyl)-N′-(4- 3H), 2.84 (t, 2H), 2.55 (q, 4H), 1.48 (s,4H), fluorophenyl)cyclopropane-1,1- 1.39 (t, 6H). dicarboxamide 19N-(4-{[7-{[3-(4-acetylpiperazin- ¹H NMR (400 MHz, CDCl₃): 10.04 (s, 1H),1-yl)propyl]oxy}-6- 8.48-8.47 (d, 1H), 8.21 (s, 1H), 7.79-7.76 (d,(methyloxy)quinolin-4-yl]oxy}- 1H), 7.57 (s, 1H), 7.52-7.44 (m, 3H),3-fluorophenyl)-N′-(4- 7.28-7.20 (m, 2H), 7.09-7.05 (t, 2H), 6.40-6.39(d, 1H), fluorophenyl)cyclopropane-1,1- 4.30-4.26 (t, 2H), 4.04 (s, 3H),3.64-3.62 (t, dicarboxamide 2H), 3.49-3.47 (t, 2H), 2.62-2.58 (t, 2H),2.50-2.44 (m, 4H), 2.17-2.12 (m, 2H), 2.10 (s, 3H), 1.84-1.81 (t, 2H),1.64-1.61 (t, 2H). 20 1,1-dimethylethyl 4-(3-{[4-[(2- ¹H NMR (400 MHz,DMSO-d₆): 10.54 (s, 1H), fluoro-4-{[((1R,2R)-1-{[(4- 9.72 (s, 1H),8.47-8.46 (d, 1H), 7.96-7.93 (dd, fluorophenyl)amino]carbonyl}- 1H),7.63-7.61 (m, 2H), 7.52 (br s, 2H), 2-methylcyclopropyl) 7.42-7.40 (d,2H), 7.17-7.12 (t, 2H), 6.44-6.42 (d, carbonyl]amino}phenyl)oxy]-6- 1H),4.22-4.18 (t, 2H), 3.95 (s, 3H), (methyloxy)quinolin-7- 3.42-3.40 (m,2H), 2.36-2.26 (m, 8H), 2.00-1.98 (m, 3H), yl]oxy}propyl)piperazine-1-1.58-1.54 (m, 2H), 1.40 (s, 9H), 1.10-1.09 (d, carboxylate 3H). 21N-(4-{[6,7- 1H NMR (DMSO-d6): 10.0 (s, 1H), 9.9 (s,bis(methyloxy)quinolin-4- 1H), 8.45 (d, 1H), 7.8 (d, 2H), 7.7 (m, 2H),yl]oxy}phenyl)-N′-(4- 7.5 (s, 1H), 7.4 (s, 1H), 7.48-7.15 (m, 9H), 3.95(s, fluorophenyl)-1- 6H), 3.7 (s, 4H), 3.6 (s, 2H).(phenylmethyl)azetidine-3,3- dicarboxamide 22 N-(4-{[6,7- 1H NMR(DMSO-d6): 8.46 (d, 1H), 7.84 (d, bis(methyloxy)quinolin-4- 2H), 7.70(m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), yl]oxy}phenyl)-N′-(4- 7.24 (d, 2H),7.20 (t, 2H), 6.44 (d, 1H), 4.03 (s, fluorophenyl)azetidine-3,3- 4H),3.95 (s, 6H), 1.90 (s, 3H, acetate salt). dicarboxamide 23(1R,2S)—N-{3-fluoro-4-[(6- ¹H NMR (400 MHz, DMSO-d₆): 10.26 (s, 1H),(methyloxy)-7-{[3-(4- 9.75 (s, 1H), 8.47-8.46 (d, 1H), 7.91-7.87 (dd,methylpiperazin-1- 1H), 7.70-7.66 (m, 2H), 7.56-7.51 (m, 2H),yl)propyl]oxy}quinolin-4- 7.43-7.38 (m, 2H), 6.42-6.41 (d, 1H),yl)oxy]phenyl}-N′-(4- 4.20-4.16 (t, 2H), 3.95 (s, 3H), 2.47-2.43 (m,2H), fluorophenyl)-2- 2.40-2.24 (m, 5H), 2.14 (s, 3H), 2.03-1.93 (m,3H), methylcyclopropane-1,1- 1.89 (s, 3H), 1.45-1.42 (m, 1H), 1.38-1.35(m, dicarboxamide 1H), 1.10-1.08 (d, 3H). 24 (1R,2R)—N-{3-fluoro-4-[(6-¹H NMR (400 MHz, DMSO-d₆): 10.56 (s, 1H), (methyloxy)-7-{[3-(4- 9.75 (s,1H), 8.47-8.46 (d, 1H), 7.96-7.93 (d, methylpiperazin-1- 1H), 7.68-7.61(m, 2H), 7.53-7.52 (m, 2H), yl)propyl]oxy}quinolin-4- 7.44-7.39 (m, 2H),7.18-7.12 (m, 2H), yl)oxy]phenyl}-N′-(4- 6.44-6.42 (d, 1H), 4.20-4.17(t, 2H), 3.95 (s, 3H), fluorophenyl)-2- 3.42-3.30 (m, 3H), 2.46-2.44 (m,2H), 2.33 (br methylcyclopropane-1,1- s, 2H), 2.15 (s, 3H), 2.05-1.94(m, 2H), 1.89 (s, dicarboxamide 5H), 1.40-1.35 (m, 1H), 1.10-1.09 (m,3H). 25 (1R,2R)—N-[3-fluoro-4-({6- ¹H NMR (400 MHz, DMSO-d₆): 10.55 (s,1H), (methyloxy)-7-[(3-piperazin-1- 9.72 (s, 1H), 8.47-8.46 (d, 1H),7.96-7.93 (d, ylpropyl)oxy]quinolin-4- 1H), 7.68-7.61 (m, 2H), 7.52 (brs, 2H), yl}oxy)phenyl]-N′-(4- 7.44-7.40 (m, 2H), 7.17-7.12 (m, 2H),6.44-6.43 (d, fluorophenyl)-2- 1H), 4.21-4.18 (t, 2H), 3.95 (s, 3H),2.79 (br s, methylcyclopropane-1,1- 4H), 2.47-2.44 (t, 2H), 2.38 (br s,3H), dicarboxamide 2.04-1.95 (m, 3H), 1.40-1.35 (m, 2H), 1.11-1.09 (m,5H). 26 N-(3-fluoro-4-{[7-({3-[4-(1- ¹H NMR (400 MHz, DMSO-d₆): 10.40(s, 1H), methylethyl)piperazin-1- 10.02 (s, 1H), 8.47-8.46 (d, 1H),7.92-7.89 (d, yl]propyl}oxy)-6- 1H), 7.66-7.63 (m, 2H), 7.52-7.51 (d,2H), (methyloxy)quinolin-4- 7.44-7.39 (m, 2H), 7.19-7.14 (m, 2H),yl]oxy}phenyl)-N′-(4- 6.42-6.41 (d, 1H), 4.20-4.17 (t, 2H), 3.95 (s,3H), fluorophenyl)cyclopropane-1,1- 2.70-2.68 (m, 1H), 2.62-2.55 (m,2H), dicarboxamide 2.46-2.33 (m, 8H), 1.99-1.94 (m, 2H), 1.47 (s, 4H),1.00-0.95 (m, 6H). 27 N-(4-{[7-{[3- ¹H NMR (DMSO-d₆)10.34 (s, 1H), 10.01(s, (diethylamino)propyl]oxy}-6- 1H), 8.50 (s, 1H), 7.81 (dd, 1H),7.55-7.68 (m, (methyloxy)quinazolin-4- 2H), 7.51-7.55 (m, 2H), 7.33-7.48(m, 3H), yl]oxy}-3-fluorophenyl)-N′-(4- 7.12 (t, 2H), 4.22 (t, 2H), 3.94(s, 3H), fluorophenyl)cyclopropane-1,1- 2.52-2.61 (m, 2H), 2.49-2.51 (m,4H), 1.83-1.94 (m, dicarboxamide 2H), 1.42 (s, 4H), 0.95 (t, 6H). 28(1R,2R)—N-(4-{[7-{[3- ¹H NMR (DMSO-d₆) d 10.52 (s, 1H), 9.70 (s,(diethylamino)propyl]oxy}-6- 1H), 8.44 (d, 1H), 7.92 (dd, 1H), 7.61 (m,2H), (methyloxy)quinolin-4-yl]oxy}- 7.50 (m, 2H), 7.43 (m, 2H), 7.12 (t,2H), 3-fluorophenyl)-N′-(4- 6.41 (d, 1H), 4.17 (t, 2H), 3.93 (s, 3H),2.55 (m, fluorophenyl)-2- 2H), 2.31 (m, 4H), 1.98 (m, 1H), 1.88 (m, 2H),methylcyclopropane-1,1- 1.35 (m, 2H), 1.07 (d, 3H), 0.94 (t, 6H).dicarboxamide 29 (1R,2R)—N-(4-{[7-{[2- ¹H NMR (DMSO-d₆) d 10.52 (s, 1H),9.70 (s, (diethylamino)ethyl]oxy}-6- 1H), 8.44 (d, 1H), 7.78 (dd, 1H),7.61 (m, 2H), (methyloxy)quinolin-4-yl]oxy}- 7.51 (m, 2H), 7.41 (m, 2H),7.12 (t, 2H), 3-fluorophenyl)-N′-(4- 6.41 (d, 1H), 4.17 (t, 2H), 3.93(s, 3H), 2.85 (t, 2H), fluorophenyl)-2- 2.57 (q, 4H), 1.98 (m, 1H), 1.34(m, 2H), methylcyclopropane-1,1- 1.07 (d, 3H), 0.98 (t, 6H).dicarboxamide 30 (1R,2S)—N-(4-{[7-{[3- ¹H NMR (DMSO-d₆) d 10.17 (s, 1H),9.97 (s, (diethylamino)propyl]oxy}-6- 1H), 8.39 (d, 1H), 7.80 (dd, 1H),7.62 (m, 2H), (methyloxy)quinolin-4-yl]oxy}- 7.45 (m, 2H), 7.31 (m, 2H),7.09 (t, 2H), 3-fluorophenyl)-N′-(4- 6.34 (d, 1H), 4.12 (t, 2H), 3.88(s, 3H), 2.46 (m, fluorophenyl)-2- 2H), 2.40 (m, 4H), 1.92 (m, 1H), 1.84(m, 2H), methylcyclopropane-1,1- 1.37 (m, 1H), 1.29 (m, 1H), 1.01 (d,3H), dicarboxamide 0.89 (t, 6H). 31 (1R,2S)—N-(4-{[7-{[2- ¹H NMR(DMSO-d₆) d 10.22 (s, 1H), 10.01 (s, (diethylamino)ethyl]oxy}-6- 1H),8.44 (d, 1H), 7.86 (dd, 1H), 7.66 (m, 2H),(methyloxy)quinolin-4-yl]oxy}- 7.49 (m, 2H), 7.39 (m, 2H), 7.14 (m, 2H),3-fluorophenyl)-N′-(4- 6.39 (d, 1H), 4.18 (m, 2H), 3.92 (s, 3H), 2.85(t, fluorophenyl)-2- 2H), 2.57 (q, 4H), 1.97 (m, 1H), 1.42 (m, 1H),methylcyclopropane-1,1- 1.35 (m, 1H), 1.06 (d, 3H), 0.98 (t, 6H).dicarboxamide 32 N-(4-{[7-{[2- ¹H NMR (CDCl₃) 8.57 (s, 1H), 8.12 (s,1H), (diethylamino)ethyl]oxy}-6- 7.73-7.81 (m, 2H), 7.48-7.53 (m, 2H),7.32 (s, (methyloxy)quinazolin-4- 1H), 6.98-7.08 (m, 3H), 4.28 (t, 2H),4.04 (s, yl]oxy}-3-fluorophenyl)-N′-(4- 3H), 3.25 (t, 2H), 2.76 (q, 4H),2.67 (q, 4H), fluorophenyl)cyclobutane-1,1- 2.01-2.15 (m, 2H), 1.10 (t,6H). dicarboxamide 33 (1R,2S)—N-[3-fluoro-4-({6- ¹H NMR (400 MHz,DMSO-d₆): 10.28 (s, 1H), (methyloxy)-7-[(3-piperazin-1- 9.80 (s, 1H)8.47-8.46 (d, 1H), 7.90-7.88 (d, ylpropyl)oxy]quinolin-4- 1H), 7.70-7.62(m, 2H), 7.56-7.52 (m, 2H), yl}oxy)phenyl]-N′-(4- 7.44-7.39 (m, 2H),7.18-7.12 (m, 2H), fluorophenyl)-2- 6.44-6.41 (t, 1H), 4.20-4.17 (t,2H), 3.95 (s, 3H), methylcyclopropane-1,1- 2.74-2.72 (t, 3H), 2.46-2.42(m, 1H), 2.35 (br s, dicarboxamide 3H), 2.03-1.93 (m, 3H), 1.87 (s, 4H),1.43-1.35 (m, 2H), 1.09-1.08 (m, 3H). 34 (1r,2R,3S)—N-[3-fluoro-4-({6-1H NMR (DMSO-d6): 1H (10.12 ppm, s), (methyloxy)-7-[(3-morpholin-4- 1H(9.6 ppm, s), 1H (8.46 ppm, d), 1H (7.88 ppm, ylpropyl)oxy]quinolin-4-dd), 2H (7.68 ppm, m), 1H (7.56 ppm, d), yl}oxy)phenyl]-N′-(4- 1H (7.51ppm, s), 2H (7.4 ppm, m), 2H (7.13 ppm, fluorophenyl)-2,3- t), 1H (6.4ppm, d), 2H (4.2 ppm, t), 3H (3.94 ppm, dimethylcyclopropane-1,1- s), 4H(3.6 ppm, t), 2H (2.45 ppm, t), dicarboxamide 4H (2.37 ppm, m), 2H (1.97ppm, t), 2H (1.8 ppm, m), 6H (1.28 ppm, d). 35(1r,2R,3S)—N-{3-fluoro-4-[(6- 1H NMR (DMSO-d6): 1H (10.12 ppm, s),(methyloxy)-7-{[3-(4- 1H (9.6 ppm, s), 1H (8.46 ppm, d), 1H (7.88 ppm,methylpiperazin-1- dd), 2H (7.69 ppm, m), 1H (7.58 ppm, d),yl)propyl]oxy}quinolin-4- 1H (7.51 ppm, s), 2H (7.4 ppm, m), 2H (7.13ppm, yl)oxy]phenyl}-N′-(4- t), 1H (6.4 ppm, d), 2H (4.2 ppm, t), 3H(3.95 ppm, fluorophenyl)-2,3- s), 10H (2.35 ppm, m), 3H (2.14 ppm, s),dimethylcyclopropane-1,1- 2H (1.97 ppm, t), 2H (1.8 ppm, m), 6H (1.28ppm, dicarboxamide d). 36 N-[3-fluoro-4-({6-(methyloxy)- ¹H NMR (400MHz, DMSO-d6): 8.45 (d, 2H), 7-[(3-morpholin-4- 8.15 (d, 1H), 7.8 (d,1H), 7.45 (m, 3H), ylpropyl)oxy]quinazolin-4- 7.25 (m, 3H), 7.0 (m, 2H),4.20 (t, 2H), 4.0 (s, 3H), yl}oxy)phenyl]-N′-(4- 3.7 (m, 4H), 2.67 (m,4H), 2.45 (m, 6H), fluorophenyl)cyclobutane-1,1- 2.0 (m, 4H).dicarboxamide 37 (2R,3R)—N-[3-fluoro-4-({6- ¹H NMR (400 MHz, CDCl₃) d8.44 (d, J = 5.1 Hz, (methyloxy)-7-[(3-morpholin-4- 1H), 8.11 (br s,1H), 7.77-7.70 (m, 2H), ylpropyl)oxy]quinolin-4- 7.53 (s, 1H), 7.50-7.44(m, 2H), 7.40 (s, 1H), yl}oxy)phenyl]-N′-(4- 7.22-7.16 (m, 2H),7.06-6.98 (m, 2H), fluorophenyl)-2,3- 6.36 (br d, J = 5.1 Hz, 1H), 4.26(t, J = 7.0 Hz, 2H), dimethylcyclopropane-1,1- 4.02 (s, 3H), 3.72 (t, J= 4.4 Hz, 4H), 2.57 (t, J = 7.3 Hz, dicarboxamide 2H), 2.50-2.42 (m,4H), 2.18-2.10 (m, 2H), 1.80-1.66 (m, 2H), 1.30-1.24 (m, 6H). 38(2R,3R)—N-(4-{[7-{[3- ¹H NMR (400 MHz, DMSO-d₆) d 10.34 (s, 1H),(diethylamino)propyl]oxy}-6- 10.05 (s, 1H), 8.46 (br s, 1H), 7.93 (br d,J = 4.7 Hz, (methyloxy)quinolin-4-yl]oxy}- 1H), 7.54-7.52 (m, 2H),3-fluorophenyl)-N′-(4- 7.52-7.50 (m, 2H), 7.50-7.30 (m, 2H), 7.20-7.10(m, 2H), fluorophenyl)-2,3- 6.47 (br s, 1H), 4.30-4.20 (m, 2H), 3.95 (s,dimethylcyclopropane-1,1- 3H), 3.40-3.10 (m, 6H), 2.60-2.40 (m, 2H),dicarboxamide 1.90-1.80 (m, 2H), 1.30-1.10 (m, 12H). 39 N-(4-{[7-{[3- 1HNMR (400 MHz, DMSO-d6): d 10.47 (s, (diethylamino)propyl]oxy}-6- 1H),10.16 (s, 1H), 8.43 (d, 1H), 7.92 (dd, 1H),(methyloxy)quinolin-4-yl]oxy}- 7.67 (m, 2H), 7.58 (m, 1H), 7.52 (s, 1H),3-fluorophenyl)-N′-(4- 7.41 (m, 2H), 7.15 (t, 2H), 6.44 (d, 1H), 4.25(t, 2H), fluorophenyl)-2,2- 3.95 (s, 3H), 3.10 (m, 6H), 2.17 (m, 2H),dimethylcyclopropane-1,1- 1.91 (s, 3H, acetate salt), 1.52 (m, 2H), 1.18(m, dicarboxamide 12H). 40 N-[3-fluoro-4-({6-(methyloxy)- 1H NMR (400MHz, DMSO-d6): d 10.21 (s, 7-[(3-morpholin-4- 1H), 9.97 (s, 1H), 8.51(s, 1H), 7.81 (dd, 1H), ylpropyl)oxy]quinazolin-4- 7.64 (m, 2H), 7.54(s, 1H), 7.48 (m, 1H), yl}oxy)phenyl]-N′-(4- 7.41 (m, 1H), 7.38 (s, 1H),7.15 (t, 2H), 4.24 (t, 2H), fluorophenyl)-2,2- 3.97 (s, 3H), 3.58 (m,4H), 2.45 (t, 2H), dimethylcyclopropane-1,1- 2.38 (m, 4H), 1.97 (m, 2H),1.58 (m, 2H), 1.18 (s, dicarboxamide 3H), 1.17 (s, 3H). 41(1R,2R,3S)—N-(4-{[7-{[2- 1H NMR (400 MHz, DMSO-d6): d 10.14 (s,(diethylamino)ethyl]oxy}-6- 1H), 9.61 (s, 1H), 8.46 (d, 1H), 7.87 (dd,1H), (methyloxy)quinolin-4-yl]oxy}- 7.67 (m, 2H), 7.57 (m, 1H), 7.51 (s,1H), 3-fluorophenyl)-N′-(4- 7.42 (s, 1H), 7.39 (m, 1H), 7.15 (t, 2H),6.41 (d, fluorophenyl)-2,3- 1H), 4.20 (m, 2H), 3.94 (s, 3H), 2.87 (m,2H), dimethylcyclopropane-1,1- 2.60 (m, 4H), 1.80 (m, 2H), 1.18 (s, 3H),dicarboxamide 1.17 (s, 3H), 1.01 (m, 6H). Note: 0.5eq of AcOH is presentby NMR. 42 N-(4-{[7-{[2- 1H NMR (400 MHz, DMSO): d 10.24 (s, 1H),(diethylamino)ethyl]oxy}-6- 10.00 (s, 1H), 8.54 (s, 1H), 7.84 (dd, 1H),(methyloxy)quinazolin-4- 7.66 (m, 2H), 7.56 (s, 1H), 7.51 (m, 1H), 7.43(m, yl]oxy}-3-fluorophenyl)-N′-(4- 2H), 7.18 (t, 2H), 4.26 (m, 2H), 3.98(s, 3H), fluorophenyl)-2,2- 2.88 (m, 2H), 2.59 (m, 4H), 1.58 (m, 2H),dimethylcyclopropane-1,1- 1.18 (s, 6H), 1.00 (t, 6H). dicarboxamide 43N-(4-{[7-{[3- 1H NMR (400 MHz, DMSO-d6): d 10.21 (s,(diethylamino)propyl]oxy}-6- 1H), 9.97 (s, 1H), 8.51 (s, 1H), 7.82 (dd,1H), (methyloxy)quinazolin-4- 7.64 (m, 2H), 7.54 (s, 1H), 7.48 (m, 1H),yl]oxy}-3-fluorophenyl)-N′-(4- 7.41 (m, 1H), 7.37 (s, 1H), 7.15 (t, 2H),4.23 (t, 2H), fluorophenyl)-2,2- 3.97 (s, 3H), 2.56 (m, 2H), 2.46 (m,4H), dimethylcyclopropane-1,1- 1.91 (m, 2H), 1.58 (m, 2H), 1.18 (s, 6H),0.96 (t, dicarboxamide 6H). 44 N-(4-{[7-{[3- 1H NMR (CDCl3): 8.57 (s,1H), 8.50 (s, 1H), (diethylamino)propyl]oxy}-6- 8.11 (s, 1H), 7.81 (dd,1H), 7.53 (m, 3H), (methyloxy)quinazolin-4- 7.28 (m, 4H), 7.04 (t, 2H),4.24 (t, 2H), 4.04 (s, 3H), yl]oxy}-3-fluorophenyl)-N′-(4- 2.95 (t, 2H),2.84 (q, 4H), 2.75 (m, 4H), fluorophenyl)cyclobutane-1,1- 2.21 (m, 2H),2.02 (m, 2H), 1.18 (t, 6H). dicarboxamide 45N-{3-fluoro-4-[(6-(methyloxy)- 1H NMR (CDCL3): 8.57 (s, 1H), 8.49 (s,1H), 7-{[3-(4-methylpiperazin-1- 8.10 (s, 1H), 7.80 (d, 1H), 7.70 (br.,1H), yl)propyl]oxy}quinazolin-4- 7.52 (m, 3H), 7.31 (m, 3H), 7.04 (t,2H), 4.26 (t, yl)oxy]phenyl}-N′-(4- 2H), 4.04 (s, 3H), 2.62-2.77 (m,14H), 2.40 (s, fluorophenyl)cyclobutane-1,1- 3H), 2.13 (m, 2H), 2.01 (m,2H). dicarboxamide 46 (2R,3R)—N-[3-fluoro-4-({6- ¹H NMR (400 MHz, CDCl₃)d 8.59 (s, 1H), (methyloxy)-7-[(3-morpholin-4- 8.11 (br s, 1H),7.80-7.76 (m, 2H), 7.53 (s, 1H), ylpropyl)oxy]quinazolin-4- 7.50-7.46(m, 2H), 7.34 (s, 1H), yl}oxy)phenyl]-N′-(4- 7.26-7.24 (m, 2H),7.06-7.00 (m, 2H), 4.28 (t, J = 6.6 Hz, fluorophenyl)-2,3- 2H), 4.05 (s,3H), 3.73 (br t, J = 4.4 Hz, 4H), dimethylcyclopropane-1,1- 2.57 (t, J =7.0 Hz, 2H), 2.52-2.45 (m, 4H), dicarboxamide 2.18-2.10 (m, 2H),1.80-1.68 (m, 2H), 1.28-1.20 (m, 6H). 47 N-(4-{[7-{[3- ¹H NMR (400 MHz,DMSO-d₆): 9.98 (s, 1H), (diethylamino)propyl]oxy}-6- 9.72 (s, 1H),8.45-8.43 (d, 1H), 7.97-7.94 (dd, (methyloxy)quinolin-4-yl]oxy}- 1H),7.73-7.69 (m, 2H), 7.65-7.52 (m, 3H), 3-fluorophenyl)-N′-(4- 7.44-7.39(m, 1H), 7.18-7.14 (m, 2H), fluorophenyl)cyclobutane-1,1- 6.43-6.42 (d,1H), 4.20-4.19 (t, 2H), 3.95 (s, 3H), dicarboxamide 2.70-2.66 (m, 6H),2.45 (br s, 2H), 1.91-1.84 (m, 6H), 0.98 (br s, 6H). 48N-{3-fluoro-4-[(6-(methyloxy)- ¹H NMR (400 MHz, DMSO-d₆): 9.99 (s, 1H),7-{[3-(4-methylpiperazin-1- 9.73 (s, 1H), 8.45-8.43 (d, 1H), 7.97-7.93(dd, yl)propyl]oxy}quinolin-4- 1H), 7.73-7.69 (m, 2H), 7.65-7.52 (m,2H), yl)oxy]phenyl}-N′-(4- 7.44-7.38 (m, 2H), 7.18-7.14 (m, 2H),fluorophenyl)cyclobutane-1,1- 6.43-6.42 (d, 1H), 4.19-4.16 (t, 3H), 3.95(s, 3H), dicarboxamide 2.70-2.66 (m, 4H), 2.47-2.33 (m, 8H), 2.15 (s,3H), 1.98-1.94 (m, 2H), 1.90-1.84 (m, 4H). 49 (2R,3R)—N-(4-{[7-{[2- ¹HNMR (400 MHz, CDCl₃) d 8.59 (br s, 1H), (diethylamino)ethyl]oxy}-6- 8.29(br s, 1H), 7.93 (s, 1H), 7.77 (d, J = 10.8 Hz, (methyloxy)quinazolin-4-1H), 7.53 (s, 1H), 7.50-7.45 (m, 2H), yl]oxy}-3-fluorophenyl)-N′-(4-7.32 (s, 1H), 7.26-7.22 (m, 2H), 7.05-6.99 (m, fluorophenyl)-2,3- 2H),4.27 (t, J = 6.6 Hz, 2H), 4.04 (s, 3H), dimethylcyclopropane-1,1- 3.03(t, J = 6.5 Hz, 2H), 2.67 (q, J = 7.0 Hz, 4H), dicarboxamide 1.80-1.70(m, 2H), 1.22 (br t, J = 5.3 Hz, 6H), 1.09 (br t, J = 7.2 Hz, 6H). 50(2R,3R)—N-(4-{[7-{[3- ¹H NMR (400 MHz, CDCl₃) d 8.58 (s, 1H),(diethylamino)propyl]oxy}-6- 8.40-8.36 (m, 1H), 8.02-7.96 (m, 1H),(methyloxy)quinazolin-4- 7.80-7.75 (m, 1H), 7.53 (s, 1H), 7.52-7.50 (m,2H), yl]oxy}-3-fluorophenyl)-N′-(4- 7.31 (s, 1H), 7.28-7.20 (m, 2H),7.02 (t, J = 8.5 Hz, fluorophenyl)-2,3- 2H), 4.25 (t, J = 6.3 Hz, 2H),dimethylcyclopropane-1,1- 4.04 (s, 3H), 3.00-2.90 (m, 2H), 2.88-2.80 (m,4H), dicarboxamide 2.30-2.20 (m, 2H), 1.76-1.68 (m, 2H), 1.25-1.15 (m,12H). 51 (2R,3R)—N-(4-{[7-{[2- ¹H NMR (400 MHz, CDCl₃) d 8.47 (d, J =5.2 Hz, (diethylamino)ethyl]oxy}-6- 1H), 8.17 (br s, 1H), 7.80-7.74 (m,2H), (methyloxy)quinolin-4-yl]oxy}- 7.55 (s, 1H), 7.52-7.46 (m, 2H),7.42 (s, 1H), 3-fluorophenyl)-N′-(4- 7.24-7.20 (m, 2H), 7.05 (t, J = 8.6Hz, 2H), fluorophenyl)-2,3- 6.38 (br d, J = 5.4 Hz, 1H), 4.27 (t, J =6.4 Hz, dimethylcyclopropane-1,1- 2H), 4.03 (s, 3H), 3.04 (br t, J = 7.2Hz, 2H), dicarboxamide 2.68 (q, J = 6.8 Hz, 4H), 1.80-1.68 (m, 2H), 1.26(d, J = 6.4 Hz, 6H), 1.09 (br t, J = 7.2 Hz, 6H). 52 N-(4-{[6,7- 1H NMR(DMSO-d6): 10.82 (s, 1H), 8.80 (d, bis(methyloxy)quinolin-4- 1H), 8.50(t, 1H), 7.83 (d, 2H), 7.74 (s, 1H), yl]oxy}phenyl)-N′-[(4- 7.56 (s,1H), 7.30-7.38 (m, 4H), 7.15 (t, 2H), fluorophenyl)methyl] 6.80 (d, 1H),4.32 (d, 2H), 4.04 (s, 3H), 4.03 (s, cyclopropane-1,1- 3H), 1.42 (s,4H). dicarboxamide 53 N-(4-{[6,7- 1H NMR (DMSO-d6): 10.62 (s, 1H), 8.79(d, bis(methyloxy)quinolin-4- 1H), 8.24 (t, 1H), 7.83 (d, 2H), 7.72 (s,1H), yl]oxy}phenyl)-N′-(2- 7.58 (s, 1H), 7.37 (d, 2H), 6.76 (d, 1H),4.04 (s, morpholin-4- 3H), 4.03 (s, 3H), 3.98 (m, 2H), 3.66 (m, 2H),ylethyl)cyclopropane-1,1- 3.49 (m, 4H), 3.25 (t, 2H), 3.13 (br., 2H),dicarboxamide 1.42 (d, 4H). 54 N-(4-{[6,7- 1H NMR (DMSO-d6): 10.78 (s,1H), 10.53 (s, bis(methyloxy)quinolin-4- 1H), 8.43 (d, 1H), 8.12 (d,1H), 7.82 (d, 2H), yl]oxy}phenyl)-N′-[2- 7.49 (s, 1H), 7.37 (s, 1H),7.20-7.28 (m, 3H), (piperidin-1- 7.15 (dd, 1H), 7.01 (td, 1H), 6.35 (d,1H), ylmethyl)phenyl]cyclopropane- 3.93 (s, 3H), 3.92 (s, 3H), 3.47 (s,2H), 2.17 (br., 1,1-dicarboxamide 4H), 1.49 (m, 4H), 1.41 (m, 4H), 1.32(br., 2H). 55 N-(4-{[6,7- 1H NMR (DMSO-d6): 10.98 (s, 1H), 10.56 (s,bis(methyloxy)quinolin-4- 1H), 8.42 (d, 1H), 8.10 (dd, 1H), 7.81 (m,2H), yl]oxy}phenyl)-N′-[2- 7.49 (s, 1H), 7.37 (s, 1H), 7.17-7.27 (m,4H), (pyrrolidin-1- 7.01 (td, 1H), 6.35 (d, 1H), 3.93 (s, 3H),ylmethyl)phenyl]cyclopropane- 3.92 (s, 3H), 3.61 (s, 2H), 2.30 (br.,4H), 1.47 (br., 1,1-dicarboxamide 4H), 1.43 (m, 4H). 56 N-(4-{[6,7- 1HNMR (DMSO-d6): 10.12 (s, 1H), 10.03 (s, bis(methyloxy)quinolin-4- 1H),8.44 (d, 1H), 7.74 (d, 2H), 7.57 (s, 1H), yl]oxy}phenyl)-N′-[3- 7.53 (d,1H), 7.48 (s, 1H), 7.37 (s, 1H), (morpholin-4- 7.21 (m, 3H), 6.98 (d,1H), 6.40 (d, 1H), 3.93 (s, ylmethyl)phenyl]cyclopropane- 3H), 3.92 (s,3H), 3.56 (t, 4H), 3.41 (s, 2H), 1,1-dicarboxamide 2.34 (br., 4H), 1.48(s, 4H). 57 N-(4-{[6,7- 1H NMR (DMSO-d6): 10.54 (s, 1H), 10.47 (s,bis(methyloxy)quinolin-4- 1H), 8.43 (d, 1H), 8.08 (d, 1H), 7.78 (d, 2H),yl]oxy}phenyl)-N′-[2- 7.49 (s, 1H), 7.37 (d, 1H), 7.18-7.30 (m, 4H),(morpholin-4- 7.03 (t, 1H), 6.37 (d, 1H), 3.94 (s, 3H), 3.93 (s,ylmethyl)phenyl]cyclopropane- 3H), 3.50 (s, 2H), 3.44 (br., 4H), 2.20(br., 4H), 1,1-dicarboxamide 1.48 (d, 4H). 58 N-(4-{[6,7- 1H NMR(DMSO-d6): 10.14 (s, 1H), 10.03 (s, bis(methyloxy)quinolin-4- 1H), 8.44(d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), yl]oxy}phenyl)-N′- 7.48 (s, 1H),7.37 (s, 1H), 7.27-7.31 (m, 2H), phenylcyclopropane-1,1- 7.19-7.23 (m,2H), 7.05 (t, 1H), 6.41 (d, 1H), dicarboxamide 3.93 (s, 6H), 3.92 (s,3H), 1.48 (s, 4H). 59 N-[3-(aminomethyl)phenyl]-N′- 1H NMR (400 MHz,DMSO-d6): d 10.28 (s, (4-{[6,7-bis(methyloxy) 1H), 10.19 (s, 1H), 8.77(m, 1H), 8.21 (m, 3H), quinolin-4-yl]oxy}phenyl) 7.84 (m, 2H), 7.76 (m,1H), 7.71 (m, 1H), cyclopropane-1,1- 7.58 (m, 2H), 7.38 (m, 3H), 7.19(m, 1H), 6.76 (m, dicarboxamide 1H), 4.03 (s, 6H), 3.39 (m, 2H), 1.53(m, 4H). Note: all peaks are very broad and unresolved. 60 N-(4-{[6,7-1H NMR (DMSO-d6): 10.0-10.2 (br., 2H), bis(methyloxy)quinolin-4- 8.46(d, 1H), 7.76 (d, 2H), 7.53 (m, 3H), yl]oxy}phenyl)-N′-[3- 7.39 (s, 1H),7.24 (m, 3H), 6.98 (d, 1H), 6.43 (d, (piperidin-1-ylmethyl) 1H), 3.95(s, 3H), 3.93 (s, 3H), 3.37 (s, 2H), phenyl]cyclopropane-1,1- 2.31 (br.,4H), 1.48 (m, 8H), 1.39 (br., 2H). dicarboxamide 61 N-(4-{[6,7- 1H NMR(DMSO-d6): 10.0-10.2 (br., 2H), bis(methyloxy)quinolin-4- 8.46 (d, 1H),7.77 (d, 2H), 7.59 (s, 1H), 7.53 (d, yl]oxy}phenyl)-N′-[3- 1H), 7.51 (s,1H), 7.39 (s, 1H), 7.23 (m, 3H), (pyrrolidin-1-ylmethyl) 6.99 (d, 1H),6.43 (d, 1H), 3.95 (s, 3H), 3.93 (s, phenyl]cyclopropane-1,1- 3H), 3.52(s, 2H), 2.42 (br., 4H), 1.69 (br, 4H), dicarboxamide 1.48 (s, 4H).

Assays

Kinase assays were performed by measurement of incorporation of γ-³³PATP into immobilized myelin basic protein (MBP). High binding white 384well plates (Greiner) were coated with MBP (Sigma #M-1891) by incubationof 60 ul/well of 20 μg/ml MBP in Tris-buffered saline (TBS; 50 mM TrispH 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 hours at 4° C. Plates werewashed 3× with 100 μl TBS. Kinase reactions were carried out in a totalvolume of 34 μl in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01%bovine gamma globulin (Sigma #I-5506), 10 mM MgCl₂, 1 mM DTT, 0.02%TritonX-100). Compound dilutions were performed in DMSO and added toassay wells to a final DMSO concentration of 1%. Each data point wasmeasured in duplicate, and at least two duplicate assays were performedfor each individual compound determination. Enzyme was added to finalconcentrations of 10 nM or 20 nM, for example. A mixture of unlabeledATP and γ-³³P ATP was added to start the reaction (2×10⁶ cpm of γ-³³PATP per well (3000 Ci/mmole) and either 10 μM or 30CM unlabeled ATP,typically. The reactions were carried out for 1 hour at room temperaturewith shaking. Plates were washed 7× with TBS, followed by the additionof 50 μl/well scintillation fluid (Wallac). Plates were read using aWallac Trilux counter. This is only one format of such assays, variousother formats are possible, as known to one skilled in the art.

The above assay procedure can be used to determine the IC₅₀ forinhibition and/or the inhibition constant, K_(i). The IC₅₀ is defined asthe concentration of compound required to reduce the enzyme activity by50% under the conditions of the assay. Exemplary compositions haveIC₅₀'s of, for example, less than about 100 μM, less than about 10 μM,less than about 1 μM, and further for example having IC₅₀'s of less thanabout 100 nM, and still further, for example, less than about 10 nM. TheK_(i) for a compound may be determined from the IC₅₀ based on threeassumptions. First, only one compound molecule binds to the enzyme andthere is no cooperativity. Second, the concentrations of active enzymeand the compound tested are known (i.e., there are no significantamounts of impurities or inactive forms in the preparations). Third, theenzymatic rate of the enzyme-inhibitor complex is zero. The rate (i.e.,compound concentration) data are fitted to the equation:

$V = {V_{\max}{E_{0}\left\lbrack {I - \frac{\left( {E_{0} + I_{0} + K_{d}} \right) - {\sqrt{\left( {E_{0} + I_{0} + K_{d}} \right)^{2} - {4E_{0}}}I_{0}}}{2E_{0}}} \right\rbrack}}$

where V is the observed rate, V_(max), is the rate of the free enzyme,I₀ is the inhibitor concentration, E₀ is the enzyme concentration, andK_(d) is the dissociation constant of the enzyme-inhibitor complex.

Kinase Specificity Assays:

Kinase activity and compound inhibition are investigated using one ormore of the three assay formats described below. The ATP concentrationsfor each assay are selected to be close to the Michaelis-Menten constant(KM) for each individual kinase. Dose-response experiments are performedat 10 different inhibitor concentrations in a 384-well plate format. Thedata are fitted to the following four-parameter equation:

Y=Min+(Max−Min)/(1+(X/IC₅₀)̂H)

where Y is the observed signal, X is the inhibitor concentration, Min isthe background signal in the absence of enzyme (0% enzyme activity), Maxis the signal in the absence of inhibitor (100% enzyme activity), IC₅₀is the inhibitor concentration at 50% enzyme inhibition and H representsthe empirical Hill's slope to measure the cooperativity. Typically H isclose to unity.c-Met Assay

c-Met biochemical activity was assessed using a Luciferase-CoupledChemiluminescent Kinase assay (LCCA) format as described above. Again,kinase activity was measured as the percent ATP remaining following thekinase reaction. Remaining ATP was detected byluciferase-luciferin-coupled chemiluminescence. Specifically, thereaction was initiated by mixing test compounds, 1 μM ATP, 1 μM poly-EYand 1 0 nM c-Met (baculovirus expressed human c-Met kinase domainP948-S1343) in a 20 uL assay buffer (20 mM Tris-HCL pH7.5, 10 mM MgCl₂,0.02% Triton X-100, 100 mM DTT, 2 mM MnCl₂). The mixture is incubated atambient temperature for 2 hours after which 20 uL luciferase-luciferinmix is added and the chemiluminescent signal read using a Wallac Victor²reader. The luciferase-luciferin mix consists of 50 mM HEPES, pH 7.8,8.5 ug/mL oxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100,0.25 mg/mL coenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units oflight/mL luciferase.

KDR Assay

KDR biochemical activity was assessed using a Luciferase-CoupledChemiluminescent Kinase assay (LCCA) format. Kinase activity wasmeasured as the percent ATP remaining following the kinase reaction.Remaining ATP was detected by luciferase-luciferin-coupledchemiluminescence. Specifically, the reaction was initiated by mixingtest compounds, 3 μM ATP, 1.6 μM poly-EY and 5 nM KDR (baculovirusexpressed human KDR kinase domain D807-V1356) in a 20 uL assay buffer(20 mM Tris-HCL pH7.5, 10 mM MgCl₂, 0.01% Triton X-100, 1 mM DTT, 3 mMMnCl₂). The mixture is incubated at ambient temperature for 4 hoursafter which 20 uL luciferase-luciferin mix is added and thechemiluminescent signal read using a Wallac Victor² reader. Theluciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5 ug/mLoxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mLcoenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mLluciferase.

-   -   flt-4 Assay

Biochemical activity for flt-4 was assessed using an AlphascreenTyrosine Kinase protocol. AlphaScreen™ (Perkin Elmer) technology is aproximity assay employing microparticles. Singlet oxygen derived from adonor bead following laser excitation results in chemiluminescence whenin proximity (100 Å) to an acceptor bead due to biomolecularinteractions. For the Flt-4 assay, donor beads coated with streptavidinand acceptor beads coated with PY100 anti-phosphotyrosine antibody wereused (Perkin Elmer). Biotinylated poly(Glu,Tyr) 4:1 (Perkin Elmer) wasused as the substrate. Substrate phosphorylation was measured byaddition of donor/acceptor beads by chemiluminescence followingdonor-acceptor bead complex formation. Test compounds, 5 μM ATP, 3 nMbiotinylated poly(Glu, Tyr) and 1 nM Flt-4 (baculovirus expressed humanFlt-4 kinase domain D725-R1298) were combined in a volume of 20 μL in a384-well white, medium binding microtiter plate (Greiner). Reactionmixtures were incubated for 1 hr at ambient temperature. Reactions werequenched by addition of 10 uL of 15-30 mg/mL AlphaScreen bead suspensioncontaining 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and0.03% Tween-20. After 2-16 hr incubation at ambient temperature plateswere read using an AlphaQuest reader (Perkin Elmer). IC₅₀ valuescorrelate well with those determined by radiometric assays.

flt-3 Assay

Biochemical activity for flt-3 was assessed using a Luciferase-CoupledChemiluminescent Kinase assay (LCCA) format. Kinase activity wasmeasured as the percent ATP remaining following the kinase reaction.Remaining ATP was detected by luciferase-luciferin-coupledchemiluminescence. Specifically, the reaction was initiated by mixingtest compounds, 5 μM ATP, 3 μM poly-EY and 5 nM Flt-3 (baculovirusexpressed human Flt-3 kinase domain R571-S993) in a 20 uL assay buffer(20 mM Tris-HCL pH7.5, 10 mM MgCl₂, 0.01% Triton X-100, 1 mM DTT, 2 mMMnCl₂). The mixture is incubated at ambient temperature for 3 hoursafter which 20 uL luciferase-luciferin mix is added and thechemiluminescent signal read using a Wallac Victor² reader. Theluciferase-luciferin mix consists of 50 mM HEPES, pH 7.8, 8.5 ug/mLoxalic acid (pH 7.8), 5 (or 50) mM DTT, 0.4% Triton X-100, 0.25 mg/mLcoenzyme A, 63 uM AMP, 28 ug/mL luciferin and 40,000 units of light/mLluciferase.

c-Kit Assay

c-Kit biochemical activity was assessed using AlphaScreen™ (PerkinElmer) technology, described above. Test compounds, ATP, biotinylatedpoly(Glu, Tyr) and c-Kit kinase were combined in a volume of 20 μL in a384-well white, medium binding microtiter plate (Greiner). Reactionmixtures were incubated for 1 hr at ambient temperature. Reactions werequenched by addition of 10 uL of 15-30 mg/mL AlphaScreen bead suspensioncontaining 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and0.03% Tween-20. After 16 hr incubation at ambient temperature plateswere read using an AlphaQuest reader (Perkin Elmer).

Structure Activity Relationships

Table 4 shows structure activity relationship data for selectedcompounds of the invention. Inhibition is indicated as IC₅₀ with thefollowing key: A=IC₅₀ less than 50 nM, B=IC₅₀ greater than 50 nM, butless than 500 nM, C═IC₅₀ greater than 500 nM, but less than 5000 nM, andD=IC₅₀ greater than 5,000 nM. Depending upon the functionality about thequinazoline or quinoline, exemplary compounds of the invention exhibitselectivity for any of c-Met, KDR, c-Kit, flt-3, and flt-4.Abbreviations for enzymes listed in Tables 2-3 are defined as follows:c-Met refers to hepatocyte growth factor receptor kinase; KDR refers tokinase insert domain receptor tyrosine kinase; flt-4, fms-like tyrosinekinase-4, representative of the FLK family of receptor tyrosine kinases;c-Kit, also called stem cell factor receptor or steel factor receptor;and flt-3, fms-like tyrosine kinase-3. Empty cells in the tablesindicate lack of data only.

TABLE 4 Entry Name c-Met KDR c-Kit flt3 flt4 1N-[({3-fluoro-4-[(6-(methyloxy)-7-{[(3aR,6aS)- A Aoctahydrocyclopenta[c]pyrrol-5- ylmethyl]oxy}quinazolin-4-yl)oxy]phenyl}amino)carbonothioyl]-2- phenylacetamide 2N-{[(3-fluoro-4-{[7-({[(3aR,6aS)-2- A A A Amethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-yl]oxy}phenyl)amino]carbonothioyl}-2- phenylacetamide 3N-{[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)(methyl)amino]carbonothioyl}-2- phenylacetamide 41-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Cfluorophenyl)imidazolidin-2-one 51-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C B Cfluorophenyl)-3-(phenylmethyl)imidazolidin-2-one 61-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Bfluorophenyl)-3-(phenylacetyl)imidazolidin-2-one 7 ethyl[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B C Bfluorophenyl)amino](oxo)acetate 8N-{[(4-{[6,7-bis(methyloxy)quinazolin-4-yl]amino}-3- A B C Bfluorophenyl)amino]carbonothioyl}-2- phenylacetamide 9N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N-methyl-N-(2-phenylethyl)sulfamide 10N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C B Cfluorophenyl)-3-(phenylmethyl)-1,2,4-oxadiazol-5- amine 111-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Cfluorophenyl)piperidin-2-one 12N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B B C Bfluorophenyl)-N′-(phenylmethyl)ethanediamide 13N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Bfluorophenyl)-4-phenyl-1,3-thiazol-2-amine 14N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- A A A C Afluorophenyl)-N′-(2-phenylethyl)ethanediamide 15N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Bfluorophenyl)-1-phenylmethanesulfonamide 16N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Cfluorophenyl)-2-phenylethanesulfonamide 174-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- C C C(phenylmethyl)benzenesulfonamide 184-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- C C Cmethyl-N-(phenylmethyl)benzenesulfonamide 194-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- C C C(2-phenylethyl)benzenesulfonamide 204-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- C C Cmethyl-N-(2-phenylethyl)benzenesulfonamide 214-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- C(3-phenylpropyl)benzenesulfonamide 221-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Bfluorophenyl)pyrrolidin-2-one 234-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl C (phenylmethyl)carbamate24 4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl (2- Cphenylethyl)carbamate 254-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- Cmethyl-N-(3-phenylpropyl)benzenesulfonamide 26N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B D C Cfluorophenyl)-N′-phenylethanediamide 274-{[6,7-bis(methyloxy)quinolin-4-yl]amino}-N-(3- Cphenylpropyl)benzamide 28 N-{[(3-fluoro-4-{[7-{[(2- A A A A Amethyloctahydrocyclopenta[c]pyrrol-5-yl)methyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}phenyl)amino]carbonothioyl}-2- phenylacetamide 29N-[(Z)-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)amino](imino)methyl]-2- phenylacetamide 304-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluoro-N- C[2-(phenyloxy)ethyl]benzenesulfonamide 31 This type of multiplicativenomenclature is not C supported in current version! 32N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-3-phenylpropane-1-sulfonamide 33N~2~-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)sulfonyl]-N-phenylglycinamide 34N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin- C3-yl)-2-phenylacetamide 35 N-{[(6-{[6,7-bis(methyloxy)quinolin-4- A C DC yl]oxy}pyridin-3-yl)amino]carbonothioyl}-2- phenylacetamide 366-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3- C C C benzothiazol-2-amine37 6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro- C C C1,3-benzothiazol-2-amine 38N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- B C D Bfluoro-1,3-benzothiazol-2-yl)-2-phenylacetamide 39N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C B Bfluorophenyl)-N′-(2-morpholin-4- ylethyl)ethanediamide 401,1-dimethylethyl {2-[(4-{[6,7- C bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)amino]-2- oxoethyl}(phenylmethyl)carbamate 41N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Bfluorophenyl)-N~2~-(phenylmethyl)glycinamide 42N~2~-acetyl-N-(4-{[6,7-bis(methyloxy)quinolin-4- Cyl]oxy}-3-fluorophenyl)-N~2~- (phenylmethyl)glycinamide 43N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,3- Bbenzothiazol-2-yl)-2-phenylacetamide 44 1,1-dimethylethyl {2-[(6-{[6,7-C bis(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)amino]-2-oxoethyl}(phenylmethyl)carbamate 45N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin- C3-yl)-N~2~-(phenylmethyl)glycinamide 46N~2~-acetyl-N-(6-{[6,7-bis(methyloxy)quinolin-4- Cyl]oxy}pyridin-3-yl)-N~2~- (phenylmethyl)glycinamide 47N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin- C3-yl)-3-phenylpropanamide 48N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin- C3-yl)-4-phenylbutanamide 49N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin- C3-yl)-N~2~-methyl-N~2~-(phenylmethyl)glycinamide 50N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Cfluorophenyl)-N′-{2-[4- (methyloxy)phenyl]ethyl}ethanediamide 51N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B A B B Afluorophenyl)-N~2~-methyl-N~2~- (phenylmethyl)glycinamide 52N-{[(4-{[6,7-bis(methyloxy)quinolin-4- A B B C Ayl]amino}phenyl)amino]carbonothioyl}-2- phenylacetamide 53N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cfluoro-1,3-benzothiazol-2-yl)-3-phenylpropanamide 54N-{[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A B C Bchloropyridin-3-yl)amino]carbonothioyl}-2- phenylacetamide 55N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- A B B Bfluorophenyl)-N′-(2,3-dihydro-1H-inden-1- yl)ethanediamide 56N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N′-(2,3-dihydro-1H-inden-2- yl)ethanediamide 57N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B C Cfluorophenyl)-N′-(1,2,3,4-tetrahydronaphthalen-1- yl)ethanediamide 58N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- 1470.06fluorophenyl)-N-(2-phenylethyl)-N- (phenylmethyl)sulfamide 59N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B C B Bfluorophenyl)-N~2~-(trifluoroacetyl)glycinamide 60N-{2-[(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B A A A Afluorophenyl)amino]-2-oxoethyl}benzamide 61N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}pyridin- A B B B3-yl)-N′-(4-fluorophenyl)propanediamide 62N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N′-[(2S)-1,2,3,4-tetrahydronaphthalen-2- yl]ethanediamide63 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Cfluorophenyl)-N′-[2-(4- methylphenyl)ethyl]ethanediamide 64N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B A B B Bfluorophenyl)-N′-(2-phenylpropyl)ethanediamide 65N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- A C B C Cfluorophenyl)-N′-[2-(4- chlorophenyl)ethyl]ethanediamide 66N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N,N′-bis(phenylmethyl)sulfamide 67N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N,N′-bis(2-phenylethyl)sulfamide 68 ethyl[(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)amino](oxo)acetate 69N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)-N′-(2-phenylethyl)ethanediamide 70N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A B B Cchloropyridin-3-yl)-N′-(4- fluorophenyl)propanediamide 71N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B D B Cfluorophenyl)-N′-[(2R)-1,2,3,4-tetrahydronaphthalen- 2-yl]ethanediamide72 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C C Cfluorophenyl)-N′-[2-(1-methylpyrrolidin-2- yl)ethyl]ethanediamide 73N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B B Cfluorophenyl)-N′-[2-(phenyloxy)ethyl]ethanediamide 74N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Bfluorophenyl)-N′-[2-hydroxy-1- (phenylmethyl)ethyl]urea 751-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B B B Bfluorophenyl)-3-[(4-methylphenyl)sulfonyl]-4-(phenylmethyl)imidazolidin-2-one 76N′-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- A B B B Bfluorophenyl)-N-methyl-N-(2- phenylethyl)ethanediamide 77N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B Bfluorophenyl)-N′-{[3- (trifluoromethyl)phenyl]methyl}ethanediamide 78N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- C A Bfluorophenyl)-N′-{2-[3- (trifluoromethyl)phenyl]ethyl}ethanediamide 79N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)-3-oxo-4-phenylbutanamide 80N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)-2-[3- (trifluoromethyl)phenyl]acetamide 816-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N- B[2-(phenyloxy)ethyl]-1,3-benzothiazol-2-amine 826-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N- C(2-piperidin-1-ylethyl)-1,3-benzothiazol-2-amine 836-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N- Cmethyl-N-(2-phenylethyl)-1,3-benzothiazol-2-amine 846-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N- C(2-pyrrolidin-1-ylethyl)-1,3-benzothiazol-2-amine 856-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N- C{[3-(trifluoromethyl)phenyl]methyl}-1,3-benzothiazol- 2-amine 866-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5-fluoro-N- C{2-[3-(trifluoromethyl)phenyl]ethyl}-1,3-benzothiazol- 2-amine 87N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)-N′-[3- (trifluoromethyl)phenyl]propanediamide 88N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- C A B B Bfluoro-1,3-benzothiazol-2-yl)-2-[3- (trifluoromethyl)phenyl]acetamide 89N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B A B B Afluorophenyl)-N~2~-{[3- (trifluoromethyl)phenyl]methyl}glycinamide 90N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Bfluorophenyl)-N~2~-(2-phenylethyl)glycinamide 91N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B B B Afluorophenyl)-N~2~-{2-[3- (trifluoromethyl)phenyl]ethyl}glycinamide 921,1-dimethylethyl {2-[(6-{[6,7- Cbis(methyloxy)quinolin-4-yl]oxy}-5-chloropyridin-3-yl)amino]-2-oxoethyl}(phenylmethyl)carbamate 93N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)-N~2~-(phenylmethyl)glycinamide 94N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- C B B D Cfluoro-1,3-benzothiazol-2-yl)-2-[3,5-bis(trifluoromethyl)phenyl]acetamide 95N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A A B B Bfluoro-1,3-benzothiazol-2-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]acetamide 96N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A A A A Amethylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide 97N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N′-(1,2,3,4-tetrahydroisoquinolin-1-ylmethyl)ethanediamide 98 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-B B B A B fluorophenyl)-N′-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]ethanediamide 99N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N~2~-methyl-N~2~-{[3-(trifluoromethyl)phenyl]methyl}glycinamide 100N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N~2~-methyl-N~2~-{2-[3-(trifluoromethyl)phenyl]ethyl}glycinamide 101N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- Cfluorophenyl)-N~2~-methyl-N~2~-(2- phenylethyl)glycinamide 1021-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B B B Cfluorophenyl)-4-(phenylmethyl)imidazolidin-2-one 103N-(6-{[6,7-bis(methyloxy)quinolin-4- A C B A Cyl]oxy}pyridazin-3-yl)-N′-(4- fluorophenyl)propanediamide 104N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Bchloropyridin-3-yl)-N′-(2- chlorophenyl)propanediamide 105N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)-N′-(3- chlorophenyl)propanediamide 106N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Cchloropyridin-3-yl)-N~2~-methyl-N~2~- (phenylmethyl)glycinamide 107N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- Bchloropyridin-3-yl)-N′-(4- chlorophenyl)propanediamide 108(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4- B Byl]oxy}phenyl)-2-[(methyloxy)imino]propanamide 109(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4- B Ayl]oxy}phenyl)-2-[(ethyloxy)imino]propanamide 110(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4- B B yl]oxy}phenyl)-2-{[(phenylmethyl)oxy]imino}propanamide 111N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C C1-(phenylmethyl)prolinamide 1121-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B C B C C3-[(4-methylphenyl)sulfonyl]-4- (phenylmethyl)imidazolidin-2-one 1131-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C C4-(phenylmethyl)imidazolidin-2-one 114N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C B4-(phenylmethyl)-4,5-dihydro-1,3-oxazol-2-amine 1156,7-bis(methyloxy)-4-({4-[4-(phenylmethyl)piperazin- C C1-yl]phenyl}oxy)quinoline 1161-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C C4-(phenylmethyl)piperazin-2-one 117N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C CN~2~-(phenylmethyl)alaninamide 118N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C CN~2~-methyl-N~2~-(phenylmethyl)alaninamide 119N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C CN~2~-(phenylmethyl)leucinamide 120N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C CN~2~-methyl-N~2~-(phenylmethyl)leucinamide 121N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C CN~2~-(phenylmethyl)valinamide 122N-[5-chloro-6-({6-(methyloxy)-4-[(piperidin-4- C Cylmethyl)oxy]quinolin-7-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)propanediamide 1231-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C C4-(phenylmethyl)tetrahydropyrimidin-2(1H)-one 124N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2- phenylethyl)ethanediamide125 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A A B A Bchloropyridin-3-yl)-N′-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide126 N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- C Cchloropyridin-3-yl)-N′-(4-fluorophenyl)cyclobutane- 1,1-dicarboxamide127 N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C CN~2~-methyl-N~2~-(phenylmethyl)valinamide 128(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4- C Ayl]oxy}phenyl)-2-[(phenyloxy)imino]propanamide 129(2E)—N-(4-{[6,7-bis(methyloxy)quinolin-4- B C yl]oxy}phenyl)-2-phenyl-2-{[(phenylmethyl)oxy]imino}ethanamide 1306,7-bis(methyloxy)-4-({4-[4-(phenylmethyl)piperidin- C C1-yl]phenyl}oxy)quinoline 131N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B Bfluorophenyl)-N′-{[2-(1-methylethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl}ethanediamide 132N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B Cfluorophenyl)-N′-[(2-ethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl]ethanediamide 133 1,1-dimethylethyl4-({[4-{[3-chloro-5-({3-[(4- B Cfluorophenyl)amino]-3-oxopropanoyl}amino)pyridin-2-yl]oxy}-6-(methyloxy)quinolin-7-yl]oxy}methyl)piperidine-1-carboxylate 134N-[5-chloro-6-({6-(methyloxy)-7-[(piperidin-4- A B B Aylmethyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)propanediamide 135 N-{5-chloro-6-[(6-(methyloxy)-7-{[(1- AB B A methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]pyridin-3-yl}-N′-(4- fluorophenyl)propanediamide 136N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A A B A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide 137N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- A A A B Aylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2- phenylethyl)ethanediamide138 N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1- A A A Aylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2- phenylethyl)ethanediamide139 N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide 140 N′-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A AB methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N-methyl-N-(2- phenylethyl)ethanediamide 141N-(3-fluoro-4-{[7-({[(3aR,5r,6aS)-2- A A A A Amethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(2-phenylethyl)ethanediamide 142N-(3-fluoro-4-{[7-({[(3aR,6aS)-2- A A A A Amethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-yl]oxy}phenyl)-N′-(2-phenylethyl)ethanediamide 1432-(3,4-dihydroisoquinolin-2(1H)-yl)-N-{3-fluoro-4- A A[(6-(methyloxy)-7-{[(1-methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-2- oxoacetamide 144N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-2-oxo-2-(3-phenylpyrrolidin-1-yl)acetamide 145N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-2-oxo-2-(2-phenylmorpholin-4-yl)acetamide 146N-[2-(dimethylamino)-2-phenylethyl]-N′-[3-fluoro-4- A A B A({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 147N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2-oxo-2-phenylethyl)ethanediamide 148N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- C Cchloropyridin-3-yl)-2,2-difluoro-N′-(4- fluorophenyl)propanediamide 149N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A A A B Amethylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(phenylmethyl)ethanediamide 150N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(2-fluorophenyl)ethyl]ethanediamide 151N-[2-(3-chlorophenyl)ethyl]-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 152N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{2-[2-(methyloxy)phenyl]ethyl}ethanediamide 153N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2-pyridin-3-ylethyl)ethanediamide 154N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A B Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′- (phenylmethyl)ethanediamide155 N-{2-[2,5-bis(methyloxy)phenyl]ethyl}-N′-[3-fluoro- A A A A A4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 156N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{2-[2-(trifluoromethyl)phenyl]ethyl}ethanediamide 157N-{2-[2-(ethyloxy)phenyl]ethyl}-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 158N-[2-(2,4-dimethylphenyl)ethyl]-N′-[3-fluoro-4-({6- A B B A B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 159N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- B Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1S)-2-(4-methylphenyl)-1-phenylethyl]ethanediamide 160N-[2-(4-chlorophenyl)ethyl]-N′-[3-fluoro-4-({6- A A A A B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 161({3-fluoro-4-[(6-(methyloxy)-7-{[(1-methylpiperidin- B C4-yl)methyl]oxy}quinolin-4- yl)oxy]phenyl}amino)(oxo)acetic acid 162N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(3-fluorophenyl)ethyl]ethanediamide 163N-[2-(2-chlorophenyl)ethyl]-N′-[3-fluoro-4-({6- A A A B A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 164N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{2-[3-(methyloxy)phenyl]ethyl}ethanediamide 165N-(1,2-diphenylethyl)-N′-[3-fluoro-4-({6-(methyloxy)- A A B B C7-[(piperidin-4-ylmethyl)oxy]quinolin-4- yl}oxy)phenyl]ethanediamide 166N-[2-(2,4-dichlorophenyl)ethyl]-N′-[3-fluoro-4-({6- A B B A B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 167N-{2-[3,4-bis(methyloxy)phenyl]ethyl}-N′-[3-fluoro- A B B B4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 168N-[2-(4-ethylphenyl)ethyl]-N′-[3-fluoro-4-({6- A B B B C(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 169N-{2-[4-(ethyloxy)phenyl]ethyl}-N′-[3-fluoro-4-({6- B C B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 170N-{2-[4-(ethyloxy)-3-(methyloxy)phenyl]ethyl}-N′-[3- A B C Bfluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 171N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- B C C Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{2-[4-(phenyloxy)phenyl]ethyl}ethanediamide 172N-{2-[3-(ethyloxy)-4-(methyloxy)phenyl]ethyl}-N′-[3- A C B Bfluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 173N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2-pyridin-2-ylethyl)ethanediamide 174N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2-pyridin-4-ylethyl)ethanediamide 175N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(4-fluorophenyl)ethyl]ethanediamide 176N-[2-(2-bromophenyl)ethyl]-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 177N-[2-(2-chloro-6-fluorophenyl)ethyl]-N′-[3-fluoro-4- A A A B A({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 178N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A B Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(2R)-2-phenylpropyl]ethanediamide 179N-(2,3-dihydro-1H-inden-1-yl)-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 180 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- AB B B methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(2-methylpropyl)ethanediamide 181N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A B B B Bmethylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(3-methylbutyl)ethanediamide 182N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A A A A Amethylpiperidin-4-yl)methyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-[(2R)-2-phenylpropyl]ethanediamide 183 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A AA A A methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(2-phenylpropyl)ethanediamide 184N-(2,3-dihydro-1H-inden-2-yl)-N′-{3-fluoro-4-[(6- A A A B A(methyloxy)-7-{[(1-methylpiperidin-4- yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}ethanediamide 185N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1R)-1-phenylethyl]ethanediamide 186N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B A B Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1S)-1-phenylethyl]ethanediamide 187N-[2-(3-bromophenyl)ethyl]-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 188N-[2-(2,6-dichlorophenyl)ethyl]-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 189N-[2-(1,3-benzodioxol-5-yl)ethyl]-N′-[3-fluoro-4-({6- A A B A B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 190 N-{5-chloro-6-[(6-(methyloxy)-7-{[(1- AA B A A methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]pyridin-3-yl}-N′-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide191 N-{2-[3-bromo-4-(methyloxy)phenyl]ethyl}-N′-[3- A A B B Bfluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 192N-{2-[3,5-bis(methyloxy)phenyl]ethyl}-N′-[3-fluoro- A A A B B4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 193N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A B Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(2-methylphenyl)ethyl]ethanediamide 194N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(3-methylphenyl)ethyl]ethanediamide 195N-{2-[3-(ethyloxy)phenyl]ethyl}-N′-[3-fluoro-4-({6- A A B B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 196N-[2-(3,4-dimethylphenyl)ethyl]-N′-[3-fluoro-4-({6- A A B B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 197N-[2-(2,5-dimethylphenyl)ethyl]-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 198N-{2-[3-chloro-4-(propyloxy)phenyl]ethyl}-N′-[3- B Cfluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 199N-{2-[4-(butyloxy)-3-chlorophenyl]ethyl}-N′-[3- B Cfluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 200N-{2-[4-(1,1-dimethylethyl)phenyl]ethyl}-N′-[3- B Cfluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 201N-{2-[4-(aminosulfonyl)phenyl]ethyl}-N′-[3-fluoro-4- A B B B B({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 202N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{2-[4-hydroxy-3-(methyloxy)phenyl]ethyl}ethanediamide 203N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{2-[3-hydroxy-4-(methyloxy)phenyl]ethyl}ethanediamide 204N-[(2,4-dichlorophenyl)methyl]-N′-[3-fluoro-4-({6- A A A A B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 205N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A B A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[4- fluoro-2-(trifluoromethyl)phenyl]methyl}ethanediamide 206N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1R)-1-(4-methylphenyl)ethyl]ethanediamide 207N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[3- fluoro-4-(trifluoromethyl)phenyl]methyl}ethanediamide 208N-[(3-chloro-4-fluorophenyl)methyl]-N′-[3-fluoro-4- A A A A B({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 209N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{(1S)-1-[3-(methyloxy)phenyl]ethyl}ethanediamide 210N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1R)-1-naphthalen-2-ylethyl]ethanediamide 211N-{[4-chloro-3-(trifluoromethyl)phenyl]methyl}-N′- A A A A A[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 212N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B C Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1S)-1-(4-methylphenyl)ethyl]ethanediamide 213N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B C B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[6-(trifluoromethyl)pyridin-3-yl]methyl}ethanediamide 214N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(2-methylphenyl)methyl]ethanediamide 215N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A B Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(3-methylphenyl)methyl]ethanediamide 216N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A B A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[4- fluoro-3-(trifluoromethyl)phenyl]methyl}ethanediamide 217N-[(3,5-dichlorophenyl)methyl]-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 218N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1R)-1,2,3,4-tetrahydronaphthalen-1-yl]ethanediamide 219N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]ethanediamide 220N-cyclopentyl-N′-[3-fluoro-4-({6-(methyloxy)-7- A B B B B[(piperidin-4-ylmethyl)oxy]quinolin-4- yl}oxy)phenyl]ethanediamide 221N-[1-(4-bromophenyl)ethyl]-N′-[3-fluoro-4-({6- A B B B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 222N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A B B Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(2-fluorophenyl)methyl]ethanediamide 223N-[2-(3,4-dichlorophenyl)ethyl]-N′-[3-fluoro-4-({6- A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 224N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(4-fluorophenyl)methyl]ethanediamide 225N-[(2,3-difluorophenyl)methyl]-N′-[3-fluoro-4-({6- A A B B A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 226N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(phenyloxy)ethyl]ethanediamide 227N-(2,2-diphenylethyl)-N′-[3-fluoro-4-({6-(methyloxy)- A B B A B7-[(piperidin-4-ylmethyl)oxy]quinolin-4- yl}oxy)phenyl]ethanediamide 228N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{2-[4-(methyloxy)phenyl]ethyl}ethanediamide 229N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2- phenylpropyl)ethanediamide230 N-[2-(4-bromophenyl)ethyl]-N′-[3-fluoro-4-({6- A A B B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 231N-(4-{[7-{[(1-ethylpiperidin-4-yl)methyl]oxy}-6- A B B B B(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-2-oxo-2-(2-phenylmorpholin-4-yl)acetamide 232N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A B A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[3- fluoro-5-(trifluoromethyl)phenyl]methyl}ethanediamide 233N-[(3,5-difluorophenyl)methyl]-N′-[3-fluoro-4-({6- A A A B A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 234N-{[2-chloro-5-(trifluoromethyl)phenyl]methyl}-N′- A A B A B[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 235N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- B B B Afluorophenyl)-N′-[2-(dimethylamino)-2- phenylethyl]ethanediamide 236N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[4-(methyloxy)phenyl]methyl}ethanediamide 237N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[4-(trifluoromethyl)phenyl]methyl}ethanediamide 238N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[3-(methyloxy)phenyl]methyl}ethanediamide 239N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[3-(trifluoromethyl)phenyl]methyl}ethanediamide 240N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-({3-[(trifluoromethyl)oxy]phenyl}methyl)ethanediamide 241N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[2-(methyloxy)phenyl]methyl}ethanediamide 242N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[2-(trifluoromethyl)phenyl]methyl}ethanediamide 243N-[(3-chlorophenyl)methyl]-N′-[3-fluoro-4-({6- A A A B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 244N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-({2-[(trifluoromethyl)oxy]phenyl}methyl)ethanediamide 245N-[(2-chlorophenyl)methyl]-N′-[3-fluoro-4-({6- A A A A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 246N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-({4-[(trifluoromethyl)oxy]phenyl}methyl)ethanediamide 247N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A B A Bmethylpiperidin-4-yl)methyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-{[4-(methyloxy)phenyl]methyl}ethanediamide 248N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A B B B Bmethylpiperidin-4-yl)methyl]oxy}quinolin-4- yl)oxy]phenyl}-N′-{[4-(trifluoromethyl)phenyl]methyl}ethanediamide 249N-(4-{[7-[(azetidin-3-ylmethyl)oxy]-6- A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(2-phenylethyl)ethanediamide 250 N-(3-fluoro-4-{[7-{[(1-methylazetidin-3- AA A A A yl)methyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(2-phenylethyl)ethanediamide 251N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2-hydroxy-2-phenylethyl)ethanediamide 252N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A Cchloropyridin-3-yl)-N′-(2,4- difluorophenyl)propanediamide 253N′-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- B Cchloropyridin-3-yl)-N-(4-fluorophenyl)-N- methylpropanediamide 254N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1R)-1-phenylpropyl]ethanediamide 255N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B C Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1S)-1-phenylpropyl]ethanediamide 256N-[(3,4-difluorophenyl)methyl]-N′-[3-fluoro-4-({6- A A A B A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 257N-[(2,6-difluorophenyl)methyl]-N′-[3-fluoro-4-({6- A A A B A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 258 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- AA A A A methylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-[2-(4- fluorophenyl)ethyl]ethanediamide 259N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A B C C Bmethylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-phenylethanediamide 260N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A C B C Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(3- fluorophenyl)ethanediamide261 N-(3-chloro-4-fluorophenyl)-N′-[3-fluoro-4-({6- A C C B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 262N-[3,4-bis(methyloxy)phenyl]-N′-[3-fluoro-4-({6- A C C B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 263N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B A B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(3- methylbutyl)ethanediamide264 N-(3,3-dimethylbutyl)-N′-[3-fluoro-4-({6-(methyloxy)- A A A A B7-[(piperidin-4-ylmethyl)oxy]quinolin-4- yl}oxy)phenyl]ethanediamide 265N-[5-chloro-6-({6-(methyloxy)-7-[(3-piperidin-1- A B B A Bylpropyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)propanediamide 266N-[5-chloro-6-({6-(methyloxy)-7-[(3-morpholin-4- A B B A Bylpropyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)propanediamide 267N-(5-chloro-6-{[7-{[3-(diethylamino)propyl]oxy}-6- A B B A B(methyloxy)quinolin-4-yl]oxy}pyridin-3-yl)-N′-(4-fluorophenyl)propanediamide 268N-[(4-chlorophenyl)methyl]-N′-[3-fluoro-4-({6- A A(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 269N-{[3,5-bis(methyloxy)phenyl]methyl}-N′-[3-fluoro-4- A A A({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 270N-[(4-butylphenyl)methyl]-N′-[3-fluoro-4-({6- A B B B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 271N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(4-methylphenyl)ethyl]ethanediamide 272N-{[3,5-bis(trifluoromethyl)phenyl]methyl}-N′-[3- A A C Bfluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 273N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- B C C Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(pyrazin-2-ylmethyl)ethanediamide 274N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(pyridin-2-ylmethyl)ethanediamide 275N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(2-phenylethyl)ethanediamide 276 N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A AA A A methylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide 277N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[2- fluoro-3-(trifluoromethyl)phenyl]methyl}ethanediamide 278N-{2-[2-bromo-6-(methyloxy)phenyl]ethyl}-N′-[3- A A A A Afluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 279N-{2-[3,4-bis(methyloxy)phenyl]ethyl}-N′-[3-fluoro- B B B A B4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N- methylethanediamide 280N-{2-[5-bromo-2-(methyloxy)phenyl]ethyl}-N′-[3- A A A A Afluoro-4-({6-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 281N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A B A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-{[2- fluoro-5-(trifluoromethyl)phenyl]methyl}ethanediamide 282N-[5-chloro-6-({6-(methyloxy)-7-[(piperidin-4- A A A A Aylmethyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 283N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A B A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[1-(4-fluorophenyl)ethyl]ethanediamide 284N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A C B B Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[(1S)-2-oxo-1-(phenylmethyl)-2-pyrrolidin-1- ylethyl]ethanediamide 285N-{3-fluoro-4-[(6-(methyloxy)-7-{[(3aR,6aS)- A A A A Aoctahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide 286N-[2-(4-aminophenyl)ethyl]-N′-[3-fluoro-4-({6- A B B B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 287N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A A B A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-2-oxo-2-[4-(phenylmethyl)piperidin-1-yl]acetamide 288N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- A A A A AN′-(4-fluorophenyl)propanediamide 289N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- A A A A 5.581N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 290N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- B Cchloropyridin-3-yl)-N′-(3- fluorophenyl)propanediamide 291N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A C B A Cchloropyridin-3-yl)-N′-phenylpropanediamide 292N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- B B B A Bchloropyridin-3-yl)-N′-(4-fluorophenyl)-2,2- dimethylpropanediamide 293N-ethyl-N′-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin- A B B B B4-ylmethyl)oxy]quinolin-4- yl}oxy)phenyl]ethanediamide 294N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(1- methylethyl)ethanediamide295 N-butyl-N′-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin- A B B B B4-ylmethyl)oxy]quinolin-4- yl}oxy)phenyl]ethanediamide 296N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- B B B B Cylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-[2-(methyloxy)ethyl]ethanediamide 297N-(cyclopropylmethyl)-N′-[3-fluoro-4-({6- A B B B B(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]ethanediamide 298N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- B A B A Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(2-morpholin-4-ylethyl)ethanediamide 299N-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin-4- A B B B Bylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-2-oxo-2- pyrrolidin-1-ylacetamide300 N-ethyl-N′-[3-fluoro-4-({6-(methyloxy)-7-[(piperidin- A B C B B4-ylmethyl)oxy]quinolin-4-yl}oxy)phenyl]-N- methylethanediamide 301N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A C B B Bchloropyridin-3-yl)-N′-(phenylmethyl)cyclopropane- 1,1-dicarboxamide 302N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- C Cchloropyridin-3-yl)-N′-(2-phenylethyl)cyclopropane- 1,1-dicarboxamide303 N-{4-[(7-chloroquinolin-4-yl)oxy]-3-fluorophenyl}- A A C C BN′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 304N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 305N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A B B Achloropyridin-3-yl)-N′-phenylcyclopropane-1,1- dicarboxamide 306N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2- A B B C Bmethylpyridin-3-yl)-N′-(4-fluorophenyl)cyclopropane- 1,1-dicarboxamide307 N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A A B A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 308N-{4-[(7-chloroquinolin-4-yl)oxy]phenyl}-N′-(4- A A B C Bfluorophenyl)cyclopropane-1,1-dicarboxamide 309N-[5-chloro-6-({6-(methyloxy)-7- A C C B C[(phenylmethyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 310N-(4-{[6,7-bis(methyloxy)quinazolin-4- A A A A Ayl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 311N-(4-{[6,7-bis(methyloxy)quinazolin-4-yl]oxy}-3- A A B A Afluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 312N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- A A A A Aylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 313N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1- A A A A Aylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 314N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperidin-1- A A A B Aylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 315N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- A A A A Aylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 316N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A A A A Amethylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 317N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2- A A A C Amethylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 318N-(4-fluorophenyl)-N′-[2-methyl-6-({6-(methyloxy)-7- A A B B B[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)pyridin-3-yl]cyclopropane-1,1-dicarboxamide 319N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3- A A A A Afluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 320N-(6-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A C C B Cchloro-2-methylpyridin-3-yl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 321N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4- A A B A Aylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 322N-[3-fluoro-4-({7-(methyloxy)-6-[(3-morpholin-4- A A A A Aylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 323N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-3,5- A A B A Adifluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 324N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,5- A A A A Adifluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 325N-{3-fluoro-4-[(7-(methyloxy)-6-{[(1- A A B A Amethylpiperidin-4-yl)methyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 326N-[5-fluoro-2-methyl-4-({6-(methyloxy)-7-[(3- A A B B Bmorpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 327N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2,3,5- A A B B Btrifluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 328N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-5- A B B C Cfluoro-2-methylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 329N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2- A B B C Bchloro-5-methylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 330N-(3-fluoro-4-{[6-hydroxy-7-(methyloxy)quinolin-4- A A A A Ayl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 331N-(4-fluorophenyl)-N′-[2-methyl-4-({6-(methyloxy)-7- A A A B A[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide 332N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1- A A A A Aylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 333N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A A A A Amethylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 334N-{3-fluoro-4-[(6-(methyloxy)-7-{[(1- A A A A Amethylpiperidin-4-yl)methyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 335N-(4-fluorophenyl)-N′-[4-({6-(methyloxy)-7-[(3- A A A A Amorpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide 336N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 337N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-2- A B B C Cchloro-5-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 338N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4- C Cyl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 339N-(4-fluorophenyl)-N′-(4-{[2-methyl-6,7- C C bis(methyloxy)quinazolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 340N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4- C Cyl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 341N-(3-fluoro-4-{[2-(methylamino)-6,7- C Cbis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 342(1S,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A A B A Amorpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 343(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A A A A Amorpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 344N-(4-{[6-{[3-(diethylamino)propyl]oxy}-7- A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 345N-(4-{[6-{[2-(diethylamino)ethyl]oxy}-7- A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 346 1,1-dimethylethyl4-(3-{[4-[(2-fluoro-4-{[(1-{[(4- A A Bfluorophenyl)amino]carbonyl}cyclopropyl)carbonyl]amino}phenyl)oxy]-6-(methyloxy)quinolin-7-yl]oxy}propyl)piperazine-1-carboxylate 347(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A Amorpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 348(1R,2R)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A B(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 349N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A A(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 350N-(4-{[7-{[3-(4-acetylpiperazin-1-yl)propyl]oxy}-6- A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 351 1,1-dimethylethyl4-(3-{[4-[(2-fluoro-4-{[((1R,2R)-1- A A B{[(4-fluorophenyl)amino]carbonyl}-2-methylcyclopropyl)carbonyl]amino}phenyl)oxy]-6-(methyloxy)quinolin-7-yl]oxy}propyl)piperazine-1- carboxylate 352N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- A C CN′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3- dicarboxamide 353N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B C CN′-(4-fluorophenyl)azetidine-3,3-dicarboxamide 354(1R,2S)—N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A A Amethylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 355(1R,2R)—N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A A Amethylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 356(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A A Apiperazin-1-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 357N-(3-fluoro-4-{[7-({3-[4-(1-methylethyl)piperazin-1- A A Ayl]propyl}oxy)-6-(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1- dicarboxamide 358N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A A(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 359(1R,2R)—N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 360(1R,2R)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 361(1R,2S)—N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 362(1R,2S)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A A(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 363N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 364(1R,2S)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A A Apiperazin-1-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 365(1r,2R,3S)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A B Bmorpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 366(1r,2R,3S)—N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A B Bmethylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 367(1r,2R,3S)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- B A Bmorpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 368(1r,2R,3S)—N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A A Bmethylpiperazin-1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 369N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- B A Bylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 370(2R,3R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A A Bmorpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 371(2R,3R)—N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A B(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 372N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A B(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1- dicarboxamide 373N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- A A Cylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1- dicarboxamide 374(1r,2R,3S)—N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A B B(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 375N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A C(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1- dicarboxamide 376(1r,2R,3S)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A B B(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 377N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- A A Bylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1- dicarboxamide 378N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A B C(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1- dicarboxamide 379N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A C(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,2-dimethylcyclopropane-1,1- dicarboxamide 380N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A B(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 381N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A A Bmethylpiperazin-1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane-1,1- dicarboxamide 382N-[3-fluoro-4-({6-(methyloxy)-7-[(3-piperazin-1- A A Bylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 383(2R,3R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A A Cmorpholin-4-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1-dicarboxamide 384N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A C(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide 385N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A A Cmethylpiperazin-1-yl)propyl]oxy}quinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclobutane-1,1- dicarboxamide 386(1R,2R)—N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A A(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1- dicarboxamide 387(1R,2R)—N-{3-fluoro-4-[(6-(methyloxy)-7-{[3-(4- A A Amethylpiperazin-1-yl)propyl]oxy}quinazolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 388(2R,3R)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- B A C(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 389(2R,3R)—N-(4-{[7-{[3-(diethylamino)propyl]oxy}-6- A A B(methyloxy)quinazolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 390(1R,2R)—N-[3-fluoro-4-({6-(methyloxy)-7-[(3- A A Apiperazin-1-ylpropyl)oxy]quinazolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-2-methylcyclopropane-1,1-dicarboxamide 391(2R,3R)—N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6- A A B(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)-2,3-dimethylcyclopropane-1,1- dicarboxamide 392N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B B AN′-[(4-fluorophenyl)methyl]cyclopropane-1,1- dicarboxamide 393N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- C D BN′-(2-morpholin-4-ylethyl)cyclopropane-1,1- dicarboxamide 394N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B D BN′-[2-(piperidin-1-ylmethyl)phenyl]cyclopropane-1,1- dicarboxamide 395N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B C BN′-[2-(pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1- dicarboxamide 396N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B A AN′-[3-(morpholin-4-ylmethyl)phenyl]cyclopropane- 1,1-dicarboxamide 397N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B C BN′-[2-(morpholin-4-ylmethyl)phenyl]cyclopropane- 1,1-dicarboxamide 398N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- A A AN′-phenylcyclopropane-1,1-dicarboxamide 399N-[3-(aminomethyl)phenyl]-N′-(4-{[6,7- B A B bis(methyloxy)quinolin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide 400N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- B AN′-[3-(piperidin-1-ylmethyl)phenyl]cyclopropane-1,1- dicarboxamide 401N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- A AN′-[3-(pyrrolidin-1-ylmethyl)phenyl]cyclopropane-1,1- dicarboxamide

1. A compound according to formula XIVa:

or a pharmaceutically acceptable salt thereof, wherein: Q is CH;(R³⁰)₀₋₄ is (R³⁰)₀; R² is halo; R²⁰ is halo; and R⁵⁰ is an unsubstitutedC₁₋₆alkyl group.
 2. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein (R²)₀₋₄ is (R²)₀; andR²⁰ is chloro or fluoro.
 3. The compound according to claim 1 which isrepresented by the following structure:

or a pharmaceutically acceptable salt thereof.
 4. A compound accordingto claim 1 which is represented by one of the following structures:

or a pharmaceutically acceptable salt of any of the above structures. 5.The compound according to claim 4 which is represented by the followingstructure:

or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof.
 7. The pharmaceuticalcomposition of claim 6 which further includes an excipient.
 8. A methodof treating a disease or disorder, comprising administering to a mammalin need of the treatment a therapeutically effective amount of thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, or a composition containing a) a therapeutically effectiveamount of the compound or a pharmaceutically acceptable salt thereof;and optionally b) an excipient, wherein the disease or disorder isstomach cancer, esophageal carcinoma, kidney cancer, liver cancer,ovarian carcinoma, cervical carcinoma, large bowel cancer, small bowelcancer, brain cancer, lung cancer, bone cancer, prostate carcinoma,pancreatic carcinoma, skin cancer, Hodgkin's disease, or non-Hodgkin'slymphoma.
 9. The method according to claim 8, wherein the brain canceris glioma or glioblastoma.